Drosophila model used to explore mechanisms underlying microsatellite expansion-induced neurodegeneration

Schweizer Burguete A, Almeida S, Gao FB, Kalb R, Akins MR, Bonini NM. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. Elife. 2015 Dec 9;4. PMID: 26650351.

From the abstract: "Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in ALS/FTD and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. ... Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. ... These data suggest that expanded repeat RNAs interact with the mRNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases."

The holo'ome. Fly and mouse model of colon-microbial interplay in the context of colon cancer

Panagi M, Georgila K, Eliopoulos AG, Apidianakis Y. Constructing personalized longitudinal holo'omes of colon cancer-prone humans and their modeling in flies and mice. Oncotarget. 2015 Dec 4. PMID: 26643871.

From the abstract: "Specific host genes and intestinal microbes, dysbiosis, aberrant immune responses and lifestyle may contribute to intestinal inflammation and cancer, but each of these parameters does not suffice to explain why sporadic colon cancer develops at an old age and only in some of the people with the same profile. ... longitudinal multi-omic and personalized studies will help to pinpoint combinations of ... factors ... The intestinal holo'ome - defined as the combination of host and microbiota genomes, transcriptomes, proteomes, and metabolomes - may be imbalanced and shift to disease when the wrong host gene expression profile meets the wrong microbiota composition. ... Detrimental combinations of factors could therefore be pinpointed computationally and validated using animal models, such as mice and flies. ... treatment strategies that break these harmful combinations could be tested in clinical trials. ... we provide an overview of the literature and a roadmap to this end."

Drosophila study relevant to NTE-related motor neuron disorder reveals possible contribution of glia to pathology of the disease

Dutta S, Rieche F, Eckl N, Duch C, Kretzschmar D. Glial expression of Swiss-cheese (SWS), the Drosophila orthologue of Neuropathy Target Esterase, is required for neuronal ensheathment and function. Dis Model Mech. 2015 Dec 3. PMID: 26634819.

From the abstract: "Swiss-cheese (SWS) and its vertebrate ortholog Neuropathy Target Esterase (NTE) cause progressive neuronal degeneration in Drosophila and mice and a complex syndrome in humans that includes mental retardation, spastic paraplegia, and blindness. SWS and NTE are widely expressed in neurons but can also be found in glia ... We have used a knockdown approach to specifically address SWS function in glia ... loss of SWS in pseudocartridge glia causes the formation of multi-layered glial whorls in the lamina cortex, the first optic neuropil. This phenotype can be rescued by the expression of SWS and NTE suggesting that the glial function is conserved in the vertebrate protein. ... the loss of SWS in glia impairs neuronal function, thereby playing an important role in the phenotypes described in the sws mutant. It is therefore likely that changes in glia also contribute to the pathology observed in patients that carry mutations in NTE."

New fly model of Pitt-Hopkins syndrome (PTHS)--human TCF4 can rescue mutations in Drosophila ortholog daugherless

Tamberg L, Sepp M, Timmusk T, Palgi M. Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless. Biol Open. 2015 Nov 30. PMID: 26621827.

From the abstract: "Pitt-Hopkins syndrome (PTHS) is caused by haploinsufficiency of Transcription factor 4 (TCF4), one of the three human class I basic helix-loop-helix transcription factors called E-proteins. Drosophila has a single E-protein, Daughterless (Da), homologous to all three mammalian counterparts. ... human TCF4 can rescue Da deficiency during fruit fly nervous system development. ... We generated da transgenic fruit fly strains with corresponding missense mutations R578H, R580W, R582P and A614V found in TCF4 of PTHS patients and studied the impact of these mutations in vivo. ... All studied PTHS-associated mutations that we introduced into Da led to similar effects in vivo as the same mutations in TCF4 in vitro. ... our Drosophila models of PTHS are applicable for further studies aiming to unravel the molecular mechanisms of this disorder."

Now free in PMC--Drosophila model included in study relating microtubule acetylation to reduction of deficits caused by mutations in LRRK2

Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ, De Vos KJ. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun. 2014 Oct 15;5:5245. PMID: 25316291; PMCID: PMC4208097.

From the abstract: "Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila ... In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. ..."

Drosophila models of Parkinsons Disease included in study the traditional chinese medicine Tianma Gouteng Yin

Liu LF, Song JX, Lu JH, Huang YY, Zeng Y, Chen LL, Durairajan SS, Han QB, Li M. Tianma Gouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson's disease. Sci Rep. 2015 Nov 18;5:16862. PMID: 26578166.

From the abstract: "Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson's disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human α-synuclein transgenic Drosophila PD models. ... In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in α-synuclein transgenic Drosophila, TGY reduced the level of α-synuclein and prevented degeneration of dopaminergic neurons. ..."

Review of Drosophila a model for neuropsychopharmacology-related research

Narayanan AS, Rothenfluh A. I Believe I Can Fly!: Use of Drosophila as a Model Organism in Neuropsychopharmacology Research. Neuropsychopharmacology. 2015 Oct 30. PMID: 26576740.

From the abstract:  "... Here, we outline why we study an invertebrate organism in the context of neuropsychiatric disorders, and we discuss how we can gain insight from studies in Drosophila. ... Highlighting some translational examples, we underline the fact that their brains works more like ours than one would have anticipated."

Their Fig. 1 provides a nice graphical summary of translational approaches.

FlyRNAi: in vivo RNAi used to validate at gene level hits i...

FlyRNAi: in vivo RNAi used to validate at gene level hits i...: Talsma AD, Chaves JF, LaMonaca A, Wieczorek ED, Palladino MJ. Genome-wide screen for modifiers of Na (+) /K (+) ATPase alleles identifies cr...

Using the fly to identify new human genes associated with disorders, even when the GWAS stats are shaky

Yu J, Wu H, Wen Y, Liu Y, Zhou T, Ni B, Lin Y, Dong J, Zhou Z, Hu Z, Guo X, Sha J, Tong C. Identification of seven genes essential for male fertility through a genome-wide association study of non-obstructive azoospermia and RNA interference-mediated large-scale functional screening in Drosophila. Hum Mol Genet. 2015 Mar 1;24(5):1493-503. PMID: 25361961.

From the abstract: "Non-obstructive azoospermia (NOA) is a complex and severe condition ... In a genome-wide association study (GWAS) of NOA in Chinese men, few loci reached genome-wide significance ... Single nucleotide polymorphisms (SNPs) without genome-wide significance may also indicate genes that are essential for fertility, and multiple stage validation can lead to false-negative results. To perform large-scale functional screening of the genes surrounding these SNPs, we used in vivo RNA interference (RNAi) in Drosophila ... 7 (31.8%) of the 22 analyzed orthologous Drosophila genes were essential for male fertility. ... Our study thus demonstrates that SNPs without genome-wide significance in GWAS may also provide clues to disease-related genes and therefore warrant functional analysis."

When a lack of gene conservation becomes a plus--fly as a model of Epidermolysis Bullosa Simplex

Bohnekamp J, Cryderman DE, Paululat A, Baccam GC, Wallrath LL, Magin TM. A Drosophila Model of Epidermolysis Bullosa Simplex. J Invest Dermatol. 2015 Aug;135(8):2031-9. PMID: 25830653; PMCID: PMC4519992.

From the abstract: "The blistering skin disorder epidermolysis bullosa simplex (EBS) results from dominant mutations in keratin 5 (K5) or keratin 14 (K14) genes, encoding the intermediate filament (IF) network of basal epidermal keratinocytes. ... Drosophila lacks cytoplasmic IFs, providing a 'null' environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14(R125C) mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates ... This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for the development of EBS therapies."

Drosophila myotonic dystrophy model responds to drug used to treat human patients with the condition

Chakraborty M, Selma-Soriano E, Magny E, Couso JP, Pérez-Alonso M, Charlet-Berguerand N, Artero R, Llamusi B. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. Dis Model Mech. 2015 Oct 29. PMID: 26515653.

From the abstract: "Up to 80% of myotonic dystrophy type 1 (DM1) patients will develop cardiac abnormalities ... very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. ... Similarly to what has been reported in human DM1 patients, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function ... As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind and reduced ribonuclear formation in the Drosophila heart but rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats."

New fly model of Parkinson's disease--alteration of the fly PGC-1alpha ortholog, spargel (srl)

Merzetti EM, Staveley BE. spargel, the PGC-1α homologue, in models of Parkinson disease in Drosophila melanogaster. Free online in BMC Neurosci. 2015 Oct 26;16(1):70. PMID: 26502946; PMCID: PMC4623274.

From the abstract: "... Directed expression of [RNAi against the Drosophila PGC-1alpha ortholog spargel (srl)] in the D. melanogaster eye causes abnormal ommatidia and bristle formation ... Ddc-Gal4 mediated tissue specific expression of srl transgene constructs in D. melanogaster DA neurons causes altered lifespan and climbing ability. Expression of a srl-RNAi causes an increase in mean lifespan but a decrease in overall loco-motor ability while induced expression of srl-EY causes a severe decrease in mean lifespan and a decrease in loco-motor ability ... The reduced lifespan and climbing ability associated with a tissue specific expression of srl in DA neurons provides a new model of PD in D. melanogaster ..."

Sleep-deprived and feeling it: new use of fly as a model of sleep deprivation-related seizures

Lucey BP, Leahy A, Rosas R, Shaw PJ. A new model to study sleep deprivation-induced seizure. Free online at Sleep. 2015 May 1;38(5):777-85. PMID: 25515102.

Report of new insights into mitochondrial retrograde signaling and its impact in Leigh syndrome and Parkinson's and other neurodegenerative diseases

Cagin U, Duncan OF, Gatt AP, Dionne MS, Sweeney ST, Bateman JM. Mitochondrial retrograde signaling regulates neuronal function. Proc Natl Acad Sci U S A. 2015 Oct 21. pii: 201505036. PMID: 26489648.

From the abstract: "Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer's and Parkinson's. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. ... We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson's disease. ..."

Launch of FlyBook includes review on fly models of neurodegenerative diseases

Launch of the FlyBook resource at the journal Genetics includes this disease-relevant review:

Leeanne McGurk, Amit Berson and Nancy M. Bonini (2015) Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics.

Results of two studies suggest disruption of RNA export from nucleus is a mechansim of neurodegenation in ALS and frontodemporal dementia

Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. PMID: 26308899.

From the abstract: "The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. ... To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. ... These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. "


Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. PMID: 26308891.

From the abstract: "... A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. "

See also comment in: Fox BW, Tibbetts RS. Neurodegeneration: Problems at the nuclear pore. Nature. 2015 Sep 3;525(7567):36-7. PMID: 26308896.

Clinical trial to follow study of GABAAergic system in Fragile X syndrome using mice and flies

Braat S, Kooy RF. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology. 2015 Jan;88:48-54. PMID: 25016041.

From the abstract: "An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable ... Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated."

Funny-named "ether-a-go-go" has potentially serious impact in development of brain tumor treatments

Huang X, He Y, Dubuc AM, Hashizume R, Zhang W, Reimand J, Yang H, Wang TA, Stehbens SJ, Younger S, Barshow S, Zhu S, Cooper MK, Peacock J, Ramaswamy V, Garzia L, Wu X, Remke M, Forester CM, Kim CC, Weiss WA, James CD, Shuman MA, Bader GD, Mueller S, Taylor MD, Jan YN, Jan LY. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat Neurosci. 2015 Sep;18(9):1236-46. PMID: 26258683.

From the abstract: "... We found that the EAG2 (Ether-a-go-go 2) potassium channel has an evolutionarily conserved function for promoting brain tumor growth and metastasis ... We identified the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings illustrate the potential of targeting ion channels in cancer treatment."

A 'how-to' review--small molecule screens with fly models of neurological disorders

Poidevin M, Zhang F, Jin P. Small-molecule screening using Drosophila models of human neurological disorders. Methods Mol Biol. 2015;1263:127-38. PMID: 25618341.

From the abstract: “… Drosophila has emerged as a premiere model system for the study of human neurodegenerative diseases, due to the realization that flies and humans share many structurally and functionally related gene families. ... Here, we describe how to utilize the existing fruit fly models of human neurological disorders to identify small-molecule leads that could potentially be further developed for therapeutic use.”

Fly eye used as model of disease affecting ... eye

Fly researchers are very familiar with use of the fly eye to study aspects of diseases such as cancer, Huntington's disease, and even intellectual disability. For this report, researchers used the fly eye in a study related to degeneration of the human retina.

Kmoch S, Majewski J, Ramamurthy V, Cao S, Fahiminiya S, Ren H, MacDonald IM, Lopez I, Sun V, Keser V, Khan A, Stránecký V, Hartmannová H, Přistoupilová A, Hodaňová K, Piherová L, Kuchař L, Baxová A, Chen R, Barsottini OG, Pyle A, Griffin H, Splitt M, Sallum J, Tolmie JL, Sampson JR, Chinnery P; Care4Rare Canada, Banin E, Sharon D, Dutta S, Grebler R, Helfrich-Foerster C, Pedroso JL, Kretzschmar D, Cayouette M, Koenekoop RK. Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nat Commun. PMID: 25574898; PMCID: PMC4356490.

From the abstract: "Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. ... Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration ... PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness."

Fly model used to address role of reactive oxygen species in galactosemia

Jumbo-Lucioni PP, Ryan EL, Hopson ML, Bishop HM, Weitner T, Tovmasyan A, Spasojevic I, Batinic-Haberle I, Liang Y, Jones DP, Fridovich-Keil JL. Manganese-based superoxide dismutase mimics modify both acute and long-term outcome severity in a Drosophila melanogaster model of classic galactosemia. Antioxid Redox Signal. 2014 May 20;20(15):2361-71. PMID: 23758052; PMCID: PMC4005492.

More catching up -- fly models helping to reveal new insights into neurodegenertive diseases

Parkinson's Disease

Reviews

Gaki GS, Papavassiliou AG. Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease. Neuromolecular Med. 2014 Jun;16(2):217-30. PMID: 24522549.

Deng H, Yuan L. Genetic variants and animal models in SNCA and Parkinson disease. Ageing Res Rev. 2014 May;15:161-76. PMID: 24768741.

Research reports

Büttner S, Broeskamp F, Sommer C, Markaki M, Habernig L, Alavian-Ghavanini A, Carmona-Gutierrez D, Eisenberg T, Michael E, Kroemer G, Tavernarakis N, Sigrist SJ, Madeo F. Spermidine protects against α-synuclein neurotoxicity. Cell Cycle. 2014;13(24):3903-8. PMID: 25483063.

Siddique YH, Naz F, Jyoti S, Fatima A, Khanam S, Rahul, Ali F, Mujtaba SF, Faisal M. Effect of Centella asiatica Leaf Extract on the Dietary Supplementation in Transgenic Drosophila Model of Parkinson's Disease. Parkinsons Dis. 2014;2014:262058. PMID: 25538856; PMCID: PMC4265550.

Roy B, Jackson GR. Interactions between Tau and α-synuclein augment neurotoxicity in a Drosophila model of Parkinson's disease. Hum Mol Genet. 2014 Jun 1;23(11):3008-23. PMID:
24430504; PMCID: PMC4014195. From the abstract: "Clinical and pathological studies have suggested considerable overlap between tauopathies and synucleinopathies. Several genome-wide association studies have identified alpha-Synuclein (SNCA) and Tau (MAPT) polymorphisms as common risk factors for sporadic Parkinson's disease (PD). However, the mechanisms by which subtle variations in the expression of wild-type SNCA and MAPT influence risk for PD and the underlying cellular events that effect neurotoxicity remain unclear. To examine causes of neurotoxicity associated with the α-Syn/Tau interaction, we used the fruit fly as a model. ... "

Angeles DC, Ho P, Chua LL, Wang C, Yap YW, Ng C, Zhou Zd, Lim KL, Wszolek ZK, Wang HY, Tan EK. Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Hum Mol Genet. 2014 Jun 15;23(12):3157-65. PMID: 24459295; PMCID: PMC4030771.

Alzheimer's Disease and Tauopathies

Wacker J, Rönicke R, Westermann M, Wulff M, Reymann KG, Dobson CM, Horn U, Crowther DC, Luheshi LM, Fändrich M. Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. Acta Neuropathol Commun. 2014 Apr 11;2:43. PMID: 24725347; PMCID: PMC4029271.

Papanikolopoulou K, Skoulakis EM. Temporally distinct phosphorylations differentiate Tau-dependent learning deficits and premature mortality in Drosophila. Hum Mol Genet. 2015 Apr 1;24(7):2065-77. doi: 10.1093/hmg/ddu726. PMID: 25524708.

Santa-Maria I, Alaniz ME, Renwick N, Cela C, Fulga TA, Van Vactor D, Tuschl T, Clark LN, Shelanski ML, McCabe BD, Crary JF. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest. 2015 Feb;125(2):681-6. PubMed PMID: 25574843; PMCID: PMC4319412.

Huntington's Disease

Maheshwari M, Bhutani S, Das A, Mukherjee R, Sharma A, Kino Y, Nukina N, Jana NR. Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease. Hum Mol Genet. 2014 May 15;23(10):2737-51. PMID: 24381308.

Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K, Xiao J, Dijkstra S, de Pril R, Vinters HV, Faull R, Signer E, Kwak S, Marugan JJ, Botas J, Fischer DF, Svendsen CN, Munoz-Sanjuan I, Yang XW. Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease. Sci Transl Med. 2014 Dec 24;6(268):268ra178. PMID: 25540325.

Vittori A, Breda C, Repici M, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ; REGISTRY investigators of the European Huntington's Disease Network. Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease. Hum Mol Genet. 2014 Jun 15;23(12):3129-37. PMID: 24452335; PMCID: PMC4030768.

ALS

King IN, Yartseva V, Salas D, Kumar A, Heidersbach A, Ando DM, Stallings NR, Elliott JL, Srivastava D, Ivey KN. The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex. J Biol Chem. 2014 May 16;289(20):14263-71. PMID: 24719334; PMCID: PMC4022891.

SMA

Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, Gonzalez MA, Scoto M, Phadke R, Sewry CA, Houlden H, Jordanova A, Tournev I, Chamova T, Litvinenko I, Zuchner S, Herrmann DN, Blake J, Sowden JE, Acsadi G, Rodriguez ML, Menezes MP, Clarke NF, Auer Grumbach M, Bullock SL, Muntoni F, Reilly MM, North KN. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain. 2015 Feb;138(Pt 2):293-310. PMID: 25497877; PMCID: PMC4306822.

Additional relevant to neurodegenerative disease

Manayi A, Saeidnia S, Gohari AR, Abdollahi M. Methods for the discovery of new anti-aging products--targeted approaches. Expert Opin Drug Discov. 2014 Apr;9(4):383-405. PMID: 24494592.

Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 2015 Jan 15;160(1-2):177-90. PMID: 25594180; PMCID: PMC4377295. From the abstract: "Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia ... "

New fly model of Leigh syndrome

Da-Rè C, von Stockum S, Biscontin A, Millino C, Cisotto P, Zordan MA, Zeviani M, Bernardi P, De Pittà C, Costa R. Leigh syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing. J Biol Chem. 2014 Oct 17;289(42):29235-46. PMID: 25164807; PMCID: PMC4200275.

From the abstract: "Leigh Syndrome (LS) is the most common early-onset, progressive mitochondrial encephalopathy usually leading to early death. The single most prevalent cause of LS is occurrence of mutations in the SURF1 gene, and LS(Surf1) patients show a ubiquitous and specific decrease in the activity of mitochondrial respiratory chain complex IV (cytochrome c oxidase, COX). SURF1 encodes an inner membrane mitochondrial protein involved in COX assembly. We established a Drosophila melanogaster model of LS based on the post-transcriptional silencing of CG9943, the Drosophila homolog of SURF1. ... We conclude that Surf1 is essential for COX activity and mitochondrial function in D. melanogaster, thus providing a new tool that may help clarify the pathogenic mechanisms of LS."

Just a little more human--report describes modification of fly alpha-conotoxin receptor--relevant to neuronal disease modeling

Heghinian MD, Mejia M, Adams DJ, Godenschwege TA, Marí F. Inhibition of cholinergic pathways in Drosophila melanogaster by α-conotoxins. FASEB J. 2015 PMID: 25466886; PMCID: PMC4422358.

FlyRNAi: One-generation in vivo Drosophila genetic screenin...

FlyRNAi: One-generation in vivo Drosophila genetic screenin...: Galindo KA, Endicott TR, Avirneni-Vadlamudi U, Galindo RL. A rapid one-generation genetic screen in a Drosophila model to capture rhabdomyos...

Tech support--Fly as cancer model--Nature Protocols paper on tumor transplants in Drosophila

Rossi F, Gonzalez C. Studying tumor growth in Drosophila using the tissue allograft method. Nat Protoc. 2015 Oct;10(10):1525-34. PMID: 26357008.

From the abstract: "This protocol describes a method to allograft Drosophila larval tissue into adult fly hosts that can be used to assay the tumorigenic potential of mutant tissues. The tissue of interest is dissected, loaded into a fine glass needle and implanted into a host. Upon implantation, nontransformed tissues do not overgrow beyond their normal size, but malignant tumors grow without limit, are invasive and kill the host. ... This method also provides an operational definition of hyperplastic, benign and malignant growth. ..."

See also a post at The Node on this 80-year-old technique:
http://thenode.biologists.com/technique-dating-back-1935-recovered-cancer-research-flies/resources/

Fly study provides "insight into why epithelial polarity is tumor-suppressive"

Bunker BD, Nellimoottil TT, Boileau RM, Classen AK, Bilder D. The transcriptional response to tumorigenic polarity loss in Drosophila. Elife. 2015 Feb 26;4. PMID: 25719210; PMCID: PMC4369581.

From the abstract: "Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. ... RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. ... We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive."

No lung? No problem. Invertebrate models in the study of lung infections.

López Hernández Y, Yero D, Pinos-Rodríguez JM, Gibert I. Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens. Front Microbiol. 2015 Feb 4;6:38. PMID: 25699030; PMCID: PMC4316775.

From the abstract: “… in vivo lung infection models performed to study lung pathologies use to be laborious, demand a great time and commonly are associated with ethical issues. When infections in experimental animals are used, they need to be refined, defined, and validated for their intended purpose. Therefore, alternative and easy to handle models of experimental infections are still needed ... Here, we review the use of … vertebrate and non-vertebrate models in the study of bacterial agents, which are considered the principal causes of lung injury. Curiously none of these animals have a respiratory system as in air-breathing vertebrates, where respiration takes place in lungs. Despite this fact, with the present review we sought to provide elements in favor of the use of these alternative animal models of infection to reveal the molecular signatures of host-pathogen interactions.”

FlyRNAi: RNA-based mitochondrial targeting technique shown ...

FlyRNAi: RNA-based mitochondrial targeting technique shown ...: Towheed A, Markantone DM, Crain AT, Celotto AM, Palladino MJ. Small mitochondrial-targeted RNAs modulate endogenous mitochondrial protein ex...

Cancer & fly models

Reitman ZJ, Sinenko SA, Spana EP, Yan H. Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila. Blood. 2015 Jan 8;125(2):336-45. PMID: 25398939; PMCID: PMC4287640.

From the abstract: “Gain-of-function mutations in nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase (IDH)1 and IDH2 frequently arise in human leukemias ... We expressed the R195H mutant of Drosophila Idh (CG7176), which is equivalent to the human cancer-associated IDH1-R132H mutant, in fly tissues ... We identified the fly homolog of D-2-hydroxyglutaric acid dehydrogenase (CG3835), which metabolizes D-2HG, and showed that coexpression of this enzyme with mutant Idh abolishes mutant Idh-associated phenotypes. These results provide a flexible model system to interrogate a cancer-related genetic and metabolic pathway ...”

Mitochondrial disease and the heart explored in fly study

Martínez-Morentin L, Martínez L, Piloto S, Yang H, Schon EA, Garesse R, Bodmer R, Ocorr K, Cervera M, Arredondo JJ. Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53-dependent apoptosis in a Drosophila cardiomyopathy model. Hum Mol Genet. 2015 Jul 1;24(13):3608-22. PMID: 25792727; PMCID: PMC4459388.

From the abstract: “... most patients with mitochondrial disease produced by defects in the oxidative phosphorylation (OXPHOS) system are susceptible to cardiac involvement. ... but the molecular mechanisms involved in cardiac impairment are unknown. One of the most frequent OXPHOS defects in humans frequently associated with cardiomyopathy is cytochrome c oxidase (COX) deficiency caused by mutations in COX assembly factors such as Sco1 and Sco2. ... we have heart specifically interfered scox expression, the single Drosophila Sco orthologue. Cardiac-specific knockdown of scox reduces fly lifespan, and it severely compromises heart function and structure, producing dilated cardiomyopathy. ... Genetic and molecular evidence strongly suggest that dp53 is directly involved in the development of the cardiomyopathy induced by scox deficiency. Remarkably, apoptosis is enhanced in the muscle and liver of Sco2 knock-out mice, clearly suggesting that cell death is a key feature of the COX deficiencies produced by mutations in Sco genes in humans.”

Fly study related to neurodegeneration, epilepsy and DOOR syndrome

Fernandes AC, Uytterhoeven V, Kuenen S, Wang YC, Slabbaert JR, Swerts J, Kasprowicz J, Aerts S, Verstreken P. Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration. J Cell Biol. 2014 Nov 24;207(4):453-62. PMID: 25422373; PMCID: PMC4242831.

From the abstract: “Synaptic demise and accumulation of dysfunctional proteins are thought of as common features in neurodegeneration. ... we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, and identify endosome-to-lysosome trafficking as a mechanism for degradation of synaptic vesicle-associated proteins. ... Our findings ... identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans.”

Catching up -- fly studies related to Huntington's disease, Alzheimer's disease and Parkinson's disease

HD

Besson MT, Alegría K, Garrido-Gerter P, Barros LF, Liévens JC. Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model. PLoS One. 2015 Mar 11;10(3):e0118765. PMID: 25761110; PMCID: PMC4356621.

From the abstract: “... Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD [Huntingtons Disease]. ... Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. ... To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. ... Our study confirms the involvement of bioenergetic deficits in HD ...”

Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J, Difiglia M, Palacino J, Wu ZY, Ma L, Botas J, Lu B. A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. Elife. 2015 Mar 4;4. doi: 10.7554/eLife.05449. PubMed PMID: 25738228; PubMed Central PMCID: PMC4372774.

From the abstract: “Huntington's disease (HD) ... is mainly caused by cytotoxicity of the mutant huntingtin protein (Htt) with an expanded polyQ stretch. While Htt is ubiquitously expressed, HD is characterized by selective neurodegeneration of the striatum. Here we report a striatal-enriched orphan G protein-coupled receptor(GPCR) Gpr52 as a stabilizer of Htt in vitro and in vivo. ... our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.”

AD

Review:

Bouleau S, Tricoire H. Drosophila models of Alzheimer's disease: advances, limits, and perspectives. J Alzheimers Dis. 2015;45(4):1015-38. PMID: 25697708.

Research articles:

Cuesto G, Jordán-Álvarez S, Enriquez-Barreto L, Ferrús A, Morales M, Acebes Á. GSK3β inhibition promotes synaptogenesis in Drosophila and mammalian neurons. PLoS One. 2015 Mar 12;10(3):e0118475. PMID: 25764078; PMCID: PMC4357437.

From the abstract: “... Alzheimer disease's patients exhibit high levels of circulating GSK3β and, consequently, pharmacological strategies based on GSK3β antagonists have been designed. The approach, however, has yielded inconclusive results so far. Here, we carried out a comparative study in Drosophila and rats addressing the role of GSK3β in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3β increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3β increases synapse density and Synapsin expression. However, experiments on younger cultures (12 days) yielded an opposite effect, a reduction of synapse density. This unexpected finding seems to unveil an age- and dosage-dependent differential response of mammalian neurons .. a feature that must be considered in the context of ... pharmacological treatments for Alzheimer's disease based on GSK3β antagonists.”

Ping Y, Hahm ET, Waro G, Song Q, Vo-Ba DA, Licursi A, Bao H, Ganoe L, Finch K, Tsunoda S. Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model. PLoS Genet. 2015 Mar 16;11(3):e1005025. PMID: 25774758; PMCID: PMC4361604.

From the abstract: “Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. ... Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. ... We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.”

PD

Review:

Vanhauwaert R, Verstreken P. Flies with Parkinson's disease. Exp Neurol. 2015 Feb 20. pii: S0014-4886(15)00043-6. PMID: 25708988.

Research articles:

van der Merwe C, Jalali Sefid Dashti Z, Christoffels A, Loos B, Bardien S. Evidence for a common biological pathway linking three Parkinson's disease-causing genes: parkin, PINK1 and DJ-1. Eur J Neurosci. 2015 May;41(9):1113-25. PMID: 25761903.

From the abstract: “Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. ...”

Zhu M, Li X, Tian X, Wu C. Mask loss-of-function rescues mitochondrial impairment and muscle degeneration of Drosophila pink1 and parkin mutants. Hum Mol Genet. 2015 Jun 1;24(11):3272-85. doi: 10.1093/hmg/ddv081. Epub 2015 Mar 5. PubMed PMID: 25743185; PubMed Central PMCID: PMC4424960.

From the abstract: “PTEN-induced kinase 1 (Pink1) and ubiquitin E3 ligase Parkin function in a linear pathway to maintain healthy mitochondria ... Mutations in the two enzymes cause the familial form of Parkinson's disease (PD) in humans, as well as accumulation of defective mitochondria and cellular degeneration in flies. Here, we show that loss of function of a scaffolding protein Mask, also known as ANKHD1 (Ankyrin repeats and KH domain containing protein 1) in humans, rescues the behavioral, anatomical and cellular defects caused by pink1 or parkin mutations in a cell-autonomous manner. ... Together, our data strongly suggest that Mask/ANKHD1 activity can be inhibited in a tissue- and timely-controlled fashion to restore mitochondrial integrity under PD-linked pathological conditions.”

NPR Morning Edition segment on fruit fly research and sleep

FlyRNAi: CRISPR + RNAi screening in Drosophila cells points...

FlyRNAi: CRISPR + RNAi screening in Drosophila cells points...: Housden BE, Valvezan AJ, Kelley C, Sopko R, Hu Y, Roesel C, Lin S, Buckner M, Tao R, Yilmazel B, Mohr SE, Manning BD, Perrimon N. Identifica...

Characterization of fly model of classic galactosemia

Jumbo-Lucioni P, Parkinson W, Broadie K. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model. Dis Model Mech. 2014 Dec;7(12):1365-78. doi: 10.1242/dmm.017137. PMID: 25326312; PMCID: PMC4257005.

From the abstract: "Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine synthesis. ... Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. ... These results reveal synaptomatrix glycosylation losses, altered trans-synaptic signaling pathway components, defective synaptogenesis and impaired coordinated movement in a CG neurological disease model."

Review--fly as model for studying role of glia in neurodegeneration

Lee YM, Sun YH. Drosophila as a model to study the role of glia in neurodegeneration. J Neurogenet. 2015 Aug 27:1-11. PMID: 26312528.

From the abstract: "Neurons and glia interact reciprocally. ... Neurodegenerative diseases are usually late-onset, progressive, and affect specific parts of the nervous system. ... The events that occur in glia, and whether and how glia participate in the pathogenesis of these diseases, have not been as well studied. In this review, we will focus on how the fruit fly Drosophila melanogaster has been used as a model to study neuron-glia interactions in neurodegenerative disorders ..."

Review--flies and prion disease

Bujdoso R, Landgraf M, Jackson WS, Thackray AM. Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response. World J Virol. 2015 Aug 12;4(3):188-97. PMID:
26279981; PMCID: PMC4534811.

From the abstract: "Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. ... Prion diseases are an important paradigm for neurodegenerative conditions in general ... Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases ... In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease."

Review--how fly research has and can continue to contribute to understanding intellectual disability

van der Voet M, Nijhof B, Oortveld MA, Schenck A. Drosophila models of early onset cognitive disorders and their clinical applications. Neurosci Biobehav Rev. 2014 Oct;46 Pt 2:326-42. PMID: 24661984.

From the abstract: "... For the extremely large, genetically and phenotypically heterogeneous group of intellectual disability (ID) disorders, more than 600 causative genes have been identified to date. However, knowledge about the molecular mechanisms and networks disrupted by these genetic aberrations is lagging behind. The fruit fly Drosophila has emerged as a powerful model organism to close this knowledge gap. This review summarizes recent achievements that have been made in this model and envisions its future contribution to our understanding of ID genetics and neuropathology. ... In conclusion, Drosophila provides many opportunities to advance future medical genomics of early onset cognitive disorders."

Review--Drosophila research contribution to understaning polyQ diseases

Xu Z, Tito A, Rui YN, Zhang S. Studying Polyglutamine Diseases in Drosophila. Exp Neurol. 2015 Aug 6. pii: S0014-4886(15)30063-7. PMID: 26257024.

From the abstract: "Polyglutamine (polyQ) diseases are a family of dominantly transmitted neurodegenerative disorders caused by an abnormal expansion of CAG trinucleotide repeats in the protein-coding regions of the respective disease-causing genes. ... Over the past two decades, Drosophila has proven to be successful in modeling this family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as ... neuronal degeneration. Additionally, it has been valuable in probing the pathogenic mechanisms, in identifying and evaluating disease modifiers, and in helping elucidate the normal functions of disease-causing genes. Knowledge learned from this simple invertebrate organism has had a large impact on our understanding of these devastating brain diseases."

Study focused on gastric cancer includes assays in flies

Caldeira J, Figueiredo J, Brás-Pereira C, Carneiro P, Moreira AM, Pinto MT, Relvas JB, Carneiro F, Barbosa M, Casares F, Janody F, Seruca R. E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade. Hum Mol Genet. 2015 Aug 5. pii: ddv312. PMID: 26246502.

From the abstract: "Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. ... To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. ..."

Fly provides genetic insights into Parkinson's associated mutations in VPS35 (PARK17)

Malik BR, Godena VK, Whitworth AJ. VPS35 pathogenic mutations confer no dominant toxicity but partial loss of function in Drosophila and genetically interact with parkin. Hum Mol Genet. 2015 Aug 6. pii: ddv322. PMID: 26251041.

From the abstract: "Mutations in VPS35 (PARK17) cause autosomal dominant, late onset Parkinson's disease (PD). ... we generated transgenic Drosophila that express variant forms of human VPS35 found in PD cases and the corresponding variants of the Drosophila ortholog. We did not find evidence of dominant toxicity ... we found that the D620N mutation confers a partial loss of function. Recently, VPS35 has been linked to the formation of mitochondria-derived vesicles, which mediate the degradation of mitochondrial proteins and contribute to mitochondrial quality control. This process is also promoted by two other PD-lined genes parkin (PARK2) and PINK1 (PARK6). We demonstrate here that vps35 genetically interacts with parkin but interestingly not with pink1. Strikingly, Vps35 overexpression is able to rescue several parkin-mutant phenotypes. Together these findings provide in vivo evidence that the D620N mutation likely confers pathogenicity through a partial loss of function mechanism and that this may be linked to other known pathogenic mechanisms such as mitochondrial dysfunction."

Studies in fly and mouse help elucidate causes and possible therapeutic for erythrokeratodermia variabilis

Tang C, Chen X, Chi J, Yang D, Liu S, Liu M, Pan Q, Fan J, Wang D, Zhang Z. Pathogenic Cx31 Is Un/misfolded to Cause Skin Abnormality via A Fos/JunB-Mediated Mechanism. Hum Mol Genet. 2015 Aug 6. PMID: 26251042.

From the abstract: "Mutations in connexin-31 (Cx31) are associated with multiple human diseases, including familial erythrokeratodermia variabilis (EKV). The pathogenic mechanism of EKV associated Cx31 mutants remains largely elusive. Here, we show that EKV pathogenic Cx31 mutants are un/misfolded and temperature sensitive. In Drosophila, expression of pathogenic Cx31, but not wildtype Cx31, causes depigmentation and degeneration of ommatidia that are rescued by expression of either dBip or dHsp70. Ectopic expression of Cx31 in mouse skin results in skin abnormalities resembling human EKV. The affected tissues show remarkable disrupted gap junction formation and significant upregulation of chaperones Bip and Hsp70 as well as AP-1 proteins c-Fos and JunB, in addition to molecular signatures of skin diseases. ..."

Proteomics analysis used to explore conserved networks relavant to Parkinson's Disease

Zhang S, Xie J, Xia Y, Yu S, Gu Z, Feng R, Luo G, Wang D, Wang K, Jiang M, Cheng X, Huang H, Zhang W, Wen T. LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration. Sci Rep. 2015 Jul 29;5:12564. doi: 10.1038/srep12564. PMID: 26220523

From the abstract: "Parkinson's disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. ..."

Fly models of Parkinson's disease used in two studies focused on LRKK2

Schreij AM, Chaineau M, Ruan W, Lin S, Barker PA, Fon EA, McPherson PS. LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation. EMBO Rep. 2015 Jan;16(1):79-86. PMID: 25427558; PMCID: PMC4304731.

From the abstract: "Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of dominant-inherited Parkinson's disease (PD), and yet we do not fully understand the physiological function(s) of LRRK2. Various components of the clathrin machinery have been recently found mutated in familial forms of PD. Here, we provide molecular insight into the association of LRRK2 with the clathrin machinery. We report that through its GTPase domain, LRRK2 binds directly to clathrin-light chains (CLCs). ... In Drosphila, a minimal rough eye phenotype caused by overexpression of Rac1, is dramatically enhanced by loss of function of CLC and LRRK2 homologues, confirming the importance of this pathway in vivo. Our data identify a new pathway in which CLCs function with LRRK2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD."

Lin CH, Li H, Lee YN, Cheng YJ, Wu RM, Chien CT. Lrrk regulates the dynamic profile of dendritic Golgi outposts through the golgin Lava lamp. J Cell Biol. 2015 Aug 3;210(3):471-83. PMID: 26216903; PMCID: PMC4523617.

From the abstract: "Constructing the dendritic arbor of neurons requires dynamic movements of Golgi outposts (GOPs), the prominent component in the dendritic secretory pathway. ... Here, we show that Leucine-rich repeat kinase (Lrrk), the Drosophila melanogaster homologue of Parkinson's disease-associated Lrrk2, regulates GOP dynamics in dendrites. ... Whereas overexpression of kinase-dead Lrrk caused dominant-negative effects on GOP dynamics, overexpression of the human LRRK2 mutant G2019S with augmented kinase activity promoted retrograde movement. Our study reveals a pathogenic pathway for LRRK2 mutations causing dendrite degeneration."

Genetic screen in Drosophila identifies molecular link betwen JNK signaling and polarity -- cancer relevance

Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Röthlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Léopold P. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature. 2015 Jun 25;522(7557):482-6. PMID: 25874673.

From the abstract: "Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd) ... Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth. "

Parkinson's disease model flies included in study related to mitochondrial function

Senyilmaz D, Virtue S, Xu X, Tan CY, Griffin JL, Miller AK, Vidal-Puig A, Teleman AA. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature. 2015 Jul 27. PMID: 26214738.

From the abstract: "Mitochondria are involved in a variety of cellular functions, ... Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. ... Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. ... Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet."

Run, sleep and thrive

Zheng L, Feng Y, Wen DT, Wang H, Wu XS. Fatiguing exercise initiated later in life reduces incidence of fibrillation and improves sleep quality in Drosophila. Age (Dordr). 2015 Aug;37(4):9816. PMID: 26206392; PMCID: PMC4512962.

From the abstract: "As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart's health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. ... We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health. "

Flies, podocytes and diabetic nephropathy

Na J, Sweetwyne MT, Park AS, Susztak K, Cagan RL. Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. Cell Rep. 2015 Jul 28;12(4):636-47. PMID: 26190114; PMCID: PMC4532696.

From the abstract: "Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly specialized component of the glomerular filtration barrier. Here, we demonstrate that the Drosophila nephrocyte, a cell analogous to the mammalian podocyte, displays defects that phenocopy aspects of diabetic nephropathy in animals fed chronic high dietary sucrose. Through functional studies, we identify an OGT-Polycomb-Knot-Sns pathway that links dietary sucrose to loss of the Nephrin ortholog Sns ..."

New fly model of ALS -- temporarl and spatial control of TDP-43 expression

Cheng CW, Lin MJ, Shen CJ. Rapamycin Alleviates Pathogenesis of a New Drosophila Model of ALS-TDP. J Neurogenet. 2015 Jul 29:1-47. PMID: 26219309.

From the abstract: "... We describe the generation and characterization of a new fly model of ALS-TDP with transgenic expression of the Drosophila ortholog of TDP-43, dTDP, in adult flies under the control of a temperature sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. ... In sum, this Drosophila model of ALS-TDP under temporal and spatial control presents a useful new genetic tool for the screening and validation of therapeutic drugs for ALS. Furthermore, the data support our previous finding that autophagy activators including rapamycin are potential therapeutic drugs for the progression of neurodegenerative diseases with TDP-43 proteinopathies."

Review--fly models of Huntington's disease

Using Drosophila models of Huntington's disease as a translatable tool. http://t.co/lXw6IQDTa4

— flypapers (@fly_papers) August 5, 2015

From the abstract: "there has been a significant contribution to our understating of the disease from studies utilizing Drosophila melanogaster. Flies have a Htt protein, so the endogenous pathways with which it interacts are likely conserved. Transgenic flies engineered to overexpress the human mutant HTT gene display protein aggregation, neurodegeneration, behavioural deficits and a reduced lifespan. The short life span of flies, low cost of maintaining stocks and genetic tools available for in vivo manipulation make them ideal for the discovery of new genes that are involved in HD pathology."

Adult fly leg as "valuable new tool" for study of TDP-43-mediated degeneration of motor neurons

Sreedharan J, Neukomm LJ, Brown RH Jr, Freeman MR. Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2. Curr Biol. 2015 Jul 28. pii: S0960-9822(15)00739-3. PMID: 26234214.

From the abstract: "The RNA-processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease [1-4]. TDP-43 is conserved in Drosophila ... We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens. We show that expression of TDP-43Q331K caused dying-back of NMJs and axons ... We report the identification of three genes that suppress TDP-43 toxicity ... In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes."

Methods review -- use of fly to model early stages of Alzheimer's disease

Lim JY, Ott S, Crowther DC. Drosophila melanogaster as a Model for Studies on the Early Stages of Alzheimer's Disease. Methods Mol Biol. 2016;1303:227-39. PMID: 26235070.

Review highlights usefulness of Drosophila as a model for study of congenital heart disease

Vogler G, Bodmer R. Cellular Mechanisms of Drosophila Heart Morphogenesis. J Cardiovasc Dev Dis. 2015 Mar 1;2(1):2-16.  PMID: 26236710

From the abstract: "Many of the major discoveries in the fields of genetics and developmental biology have been made using the fruit fly, Drosophila melanogaster. With regard to heart development, the conserved network of core cardiac transcription factors that underlies cardiogenesis has been studied in great detail in the fly, and the importance of several signaling pathways that regulate heart morphogenesis, such as Slit/Robo, was first shown in the fly model. ... The specific limitations of the various cardiac model systems currently employed (mammalian and fish models) provide a niche for the fly model ... Here, we review recent advances made using the Drosophila embryo that identify factors relevant for heart formation. ..."

New fly model of Meier-Gorlin syndrome

Maxim Balasov, Katarina Akhmetova andIgor Chesnokov. Drosophila model of Meier-Gorlin syndrome based on the mutation in a conserved C-Terminal domain of Orc6. Article first published online: 2 JUL 2015. DOI: 10.1002/ajmg.a.37214

From the abstract: "Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears, and skeletal abnormalities. Patients with MGS often carry mutations in the genes encoding the components of the pre-replicative complex such as Origin Recognition Complex (ORC) subunits Orc1, Orc4, Orc6, and helicase loaders Cdt1 and Cdc6. ... we introduced MGS mutation in Orc6 and established Drosophila model of MGS ..."

Study including fly models of Parkinson's points to possible dietary mitochondrial signal

Senyilmaz D, Virtue S, Xu X, Tan CY, Griffin JL, Miller AK, Vidal-Puig A, Teleman AA. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature. 2015 Jul 27. PMID: 26214738.

From the abstract:  "Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. ... Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. ... We find that animal cells are poised to respond to both increases and decreases in C18:0 levels... Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet."

Drosophila study suggests TNF receptor links cell polarity and neoplastic growth

Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Röthlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Léopold P. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature. 2015 Jun 25;522(7557):482-6. PMID: 25874673.

From the abstract: "Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. ... Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth. "

"At a glance" review and poster summarize results from fly and other models regarding retromer complex

Wang S, Bellen HJ. The retromer complex in development and disease. Development. 2015 Jul 15;142(14):2392-6. PMID: 26199408.

From the abstract: "The retromer complex is a multimeric protein complex involved in recycling proteins from endosomes to the trans-Golgi network or plasma membrane. ... a number of recent studies implicate aberrant retromer function in photoreceptor degeneration, Alzheimer's disease and Parkinson's disease. Here, and in the accompanying poster, we provide an overview of the molecular and cellular mechanisms of retromer-mediated protein trafficking, highlighting key examples of retromer function in vivo. "

Review of fly tools and models for the study of neurodegeneratiave diseases

Lepesant JA. The promises of neurodegenerative disease modeling. C R Biol. 2015 Jul 22. pii: S1631-0691(15)00179-1. PMID: 26210484.

From the abstract: "... This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them."

Methods chapter reviews fly as model for spetraplakin-related diseases

Hahn I, Ronshaugen M, Sánchez-Soriano N, Prokop A. Functional and genetic analysis of spectraplakins in Drosophila. In: Intermediate filament associated proteins. Methods in enzymology: Elsevier; 2015. p. in press. Corrected proof is available through the authors' institutional site.

From the abstract: "The cytoskeleton is a dynamic network of filamentous protein polymers required for virtually all cellular processes. ... One unique class of proteins, the spectraplakins, bind, regulate, and integrate the functions of ... three classes of cytoskeleton proteins. ... They have OMIM-listed disease links to epidermolysis bullosa and hereditary sensory and autonomic neuropathy (HSAN). ... To study the broad range of functions and complexity of these proteins, Drosophila is a powerful model. ... Here we use the example of Shot to illustrate how the various tools and strategies available for Drosophila can be employed to decipher and dissect cellular roles and molecular mechanisms of spectraplakins."

New study in flies and mammals related to diabetic nephropathy

Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. http://t.co/JJpcdLzpRA

— flypapers (@fly_papers) July 21, 2015

Cheaper treatment for some cancers? Results of Drosophila study and follow-up suggests it might be possible

FlyRNAi: Fly cell screen leads to findings relevant to canc...: Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate Is a JAK/STAT Pathway Inhibitor. PLoS One. 2015 Jul 1;10(7):e...

New fly models of Spinocerebellar ataxia type 17

Hsu TC, Wang CK, Yang CY, Lee LC, Hsieh-Li HM, Ro LS, Chen CM, Lee-Chen GJ, Su MT. Deactivation of TBP contributes to SCA17 pathogenesis. Hum Mol Genet. 2014 Dec 20;23(25):6878-93. PMID: 25104854.

From the abstract: "Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by the expansion of polyglutamine (polyQ) within the TATA box-binding protein (TBP). ... In this study, we generated novel Drosophila models for SCA17 that recapitulate pathological features such as aggregate formation, mobility defects and premature death. ... downregulation of TBP activity enhances retinal degeneration in SCA3 and Huntington's disease fly models, indicating that the deactivation of TBP is likely to play a common role in polyQ-induced neurodegeneration. "

Huntington's disease-related study includes work in flies--specific HTT cleavages related to toxicity

El-Daher MT, Hangen E, Bruyère J, Poizat G, Al-Ramahi I, Pardo R, Bourg N, Souquere S, Mayet C, Pierron G, Lévêque-Fort S, Botas J, Humbert S, Saudou F. Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 2015 Jul 12. pii: e201490808. PMID: 26165689.

From the abstract: "... we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies ..."

Link between Hh and zinc revealed in flies could have relevance to several human diseases

Xie J, Owen T, Xia K, Singh AV, Tou E, Li L, Arduini B, Li H, Wan LQ, Callahan B, Wang C. Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation. J Biol Chem. 2015 May 1;290(18):11591-600. PMID: 25787080; PMCID: PMC4416862.

From the abstract:  "Zinc is an essential trace element with wide-ranging biological functions, whereas the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. ... In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand."

Review--lipid physiology in worms and flies

Zhu H, Han M. Exploring developmental and physiological functions of fatty acid and lipid variants through worm and fly genetics. Annu Rev Genet. 2014;48:119-48. PMID: 25195508.

From the abstract: "Lipids are more than biomolecules for energy storage and membrane structure. With ample structural variation, lipids critically participate in nearly all aspects of cellular function. Lipid homeostasis and metabolism are closely related to major human diseases and health problems. However, lipid functional studies have been significantly underdeveloped ... Here, we review a subset of these studies using Caenorhabditis elegans and Drosophila melanogaster."

Review--Drosophila as a model for study of sleep disorders

Donelson NC, Sanyal S. Use of Drosophila in the investigation of Sleep Disorders. Exp Neurol. 2015 Jul 6. pii: S0014-4886(15)30034-0. PMID: 26160555.

From the abstract: "Genetic underpinnings for sleep disorders in humans remain poorly identified, investigated and understood. ... On the other hand, there have been steady and remarkable developments in the investigation of sleep using model organisms such as Drosophila. ... Here, we discuss the opportunities and limitations of studying sleep disorders in Drosophila and propose that a greater convergence of basic sleep research in model organisms and human genetics should catalyze better understanding of sleep disorders and generate viable therapeutic options."

Fly model points to possible new target pathway for treatment of Friedreich’s ataxia

Pablo Calap-Quintana, Sirena Soriano, José Vicente Llorens, Ismael Al-Ramahi, Juan Botas, María Dolores Moltó, María José Martínez-Sebastián. TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia. PLOS Published: July 9, 2015 DOI: 10.1371/journal.pone.0132376

From the abstract: "Friedreich’s ataxia (FRDA) ... is a multisystemic disease caused by a significant decrease in the frataxin level. ... we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. ... These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment."

Suppression of TDP-43 toxicity by newly identified factor in fly models of ALS

Chou CC, Alexeeva OM, Yamada S, Pribadi A, Zhang Y, Mo B, Williams KR, Zarnescu DC, Rossoll W. PABPN1 suppresses TDP-43 toxicity in ALS disease models. Hum Mol Genet. 2015 Jun 30. pii: ddv238. PMID: 26130692.

From the abstract: "TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. ... These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins."

Quantifying climbing defects in fly models of neurodegeneration--protocol video

Madabattula ST, Strautman JC, Bysice AM, O'Sullivan JA, Androschuk A, Rosenfelt C, Doucet K, Rouleau G, Bolduc F. Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders. J Vis Exp. 2015 Jun 13;(100). PMID: 26132637.

From the abstract: "... The assay is performed in a glass graduated cylinder, which is sealed with a wax barrier film. By increasing the threshold distance to be climbed to 17.5 cm and increasing the experiment duration to 2 min we have observed a greater sensitivity in detecting mild mobility dysfunctions. ..."

New fly model of obesity-related heart disease

Hardy CM, Birse RT, Wolf MJ, Yu L, Bodmer R, Gibbs AG. Obesity-associated Cardiac Dysfunction in Starvation-Selected Drosophila melanogaster. Am J Physiol Regul Integr Comp Physiol. 2015 Jul 1:ajpregu.00160.2015. PMID: 26136533.

Translation in fly models of CMT neuropathy

Niehues S, Bussmann J, Steffes G, Erdmann I, Köhrer C, Sun L, Wagner M, Schäfer K, Wang G, Koerdt SN, Stum M, RajBhandary UL, Thomas U, Aberle H, Burgess RW, Yang XL, Dieterich D, Storkebaum E. Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nat Commun. 2015 Jul 3;6:7520. PMID: 26138142.

Methylene blue and single oxygen explored in a fly model of tauopathy

Sheik Mohideen S, Yamasaki Y, Omata Y, Tsuda L, Yoshiike Y. Nontoxic singlet oxygen generator as a therapeutic candidate for treating tauopathies. Sci Rep. 2015 Jun 1;5:10821. PMID: 26027742; PMCID: PMC4450544.

From the abstract: "Methylene blue (MB) inhibits the aggregation of tau, a main constituent of neurofibrillary tangles. However, MB's mode of action in vivo is not fully understood. MB treatment reduced the amount of sarkosyl-insoluble tau in Drosophila that express human wild-type tau. MB concurrently ameliorated the climbing deficits of transgenic tau flies to a limited extent and diminished the climbing activity of wild-type flies. MB also decreased the survival rate of wild-type flies. Based on its photosensitive efficacies, we surmised that singlet oxygen generated through MB under light might contribute to both the beneficial and toxic effects of MB in vivo. ... Our findings indicate that singlet oxygen generators with little toxicity may be suitable drug candidates for treating tauopathies."

Review--fly models and intellectual disability

Androschuk A, Al-Jabri B, Bolduc FV. From Learning to Memory: What Flies Can Tell Us about Intellectual Disability Treatment. Front Psychiatry. 2015 Jun 3;6:85. PMID: 26089803; PMCID: PMC4453272.

From the abstract: "Intellectual disability (ID) ... affects 3% of the population and remains without pharmacological treatment. ... several model organisms have proven valuable in developing and screening candidate drugs. One such model organism is the fruit fly Drosophila. First, we review the current understanding of memory in human and its model in Drosophila. Second, we describe key signaling pathways involved ... Third, we characterize the types of memory defects found in patients with ID. Finally, we discuss how important insights gained from Drosophila learning and memory could be translated in clinical research to lead to better treatment development. "

Autophagy, retinopathy and the fly eye

Lőrincz P, Takáts S, Kárpáti M, Juhász G. iFly: The eye of the fruit fly as a model to study autophagy and related trafficking pathways. Exp Eye Res. 2015 Jun 16. pii: S0014-4835(15)00201-8. PMID: 26091788.

From the abstract: "Autophagy is a process by which eukaryotic cells degrade and recycle their intracellular components within lysosomes. Autophagy is induced by starvation to ensure survival of individual cells, and it has evolved to fulfill numerous additional roles in animals. ... Here we summarize the current knowledge of autophagy and related trafficking pathways in a convenient model: the compound eye of the fruit fly Drosophila melanogaster. In our review, we present a general introduction of the development and structure of the compound eye. This is followed by a discussion of various neurodegeneration models including retinopathies, with special emphasis on the protective role of autophagy against these diseases."

Aiming to help kids who undergo radiation therapy--fly as a model of radiation exposure

Sudmeier LJ, Howard SP, Ganetzky B. A Drosophila model to investigate the neurotoxic side effects of radiation exposure. Dis Model Mech. 2015 Jul 1;8(7):669-77. doi: 10.1242/dmm.019786. PMID: 26092528.

From the abstract: "Children undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. ... This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions."

New fly model related to myotonic dystrophy type 1 (DM1)

Bargiela A, Cerro-Herreros E, Fernandez-Costa JM, Vilchez JJ, Llamusi B, Artero R. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model. Dis Model Mech. 2015 Jul 1;8(7):679-90. PMID: 26092529.

From the abstract: "Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. ... results were validated in skeletal muscle biopsies from DM1 patients ... and also in DM1 myoblasts ... These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis."

Alzheimer's Disease and Polyphenols--review summarizes results from fly models

Jimenez-Del-Rio M, Velez-Pardo C. Alzheimer's Disease, Drosophila melanogaster and Polyphenols. Adv Exp Med Biol. 2015;863:21-53. PubMed PMID: 26092625.

From the abstract: "Alzheimer's disease (AD) is an insidious neurological disorder that affects memory, one of the human brain's main cognitive functions. Around 5.2 million Americans currently have AD, and the number threatens to climb to 7 million by 2020. Our native country, Colombia, is no exception with an estimated 260,000 individuals to be affected by AD in 2020. ... Drosophila melanogaster is increasingly being used as a valid in vivo model of AD. Here, we summarise data published within the past 16 years (1998-2014) on the molecular biology of AD and the use of polyphenols in the fly to understand the molecular actions and feasibility of these compounds in the treatment of AD."

Using SOS1 to neutralize KRAS -- fly studies contribute to characterization of new potential cancer therapeutic strategy

Leshchiner ES, Parkhitko A, Bird GH, Luccarelli J, Bellairs JA, Escudero S, Opoku-Nsiah K, Godes M, Perrimon N, Walensky LD. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1761-6. PMID: 25624485; PMCID: PMC4330742.

From the abstract: "Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼ 30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. ... The mechanism of action of SAH-SOS1 peptides was demonstrated by sequence-specific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D(V12) activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer."

Vinculin involvement in regulation of heart function during aging

Kaushik G, Spenlehauer A, Sessions AO, Trujillo AS, Fuhrmann A, Fu Z, Venkatraman V, Pohl D, Tuler J, Wang M, Lakatta EG, Ocorr K, Bodmer R, Bernstein SI, Van Eyk JE, Cammarato A, Engler AJ. Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci Transl Med. 2015 Jun 17;7(292):292ra99. PMID: 26084806.

From the abstract: "The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. ... Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. ... These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts."

Automated fly climbing assay used to uncover loci with links to A-beta-42

Liu H, Han M, Li Q, Zhang X, Wang WA, Huang F. Automated rapid iterative negative geotaxis assay and its use in a genetic screen for modifiers of Aβ(42)-induced locomotor decline in  Drosophila. Neurosci Bull. 2015 Jun 15. PMID: 26077703.

From the abstract: "The negative-geotaxis climbing assay is used to efficiently study aging and neurodegeneration in Drosophila. To make it suitable for large-scale study, a method ... has been established by simultaneously photographing the climbing of multiple groups of flies when they are manually tapped down in test tubes. Here, we automated the assay by using a well-controlled electric motor to drive the tapping, and a homemade program to analyze the climbing height of flies. ... we examined the effect of third chromosome deficiencies on the accelerated locomotor decline in Aβ42-expressing flies, and isolated 7 suppressors and 15 enhancers."

Fly study results suggest limitations to usefulness of a potential treatment for mitochondrial disorders

Kemppainen KK, Kemppainen E, Jacobs HT. The alternative oxidase AOX does not rescue the phenotype of tko25t mutant flies. G3 (Bethesda). 2014 Aug 21;4(10):2013-21. PMID: 25147191; PMCID: PMC4199707.

From the abstract: "A point mutation [technical knockout(25t) (tko(25t))] in the Drosophila gene coding for mitoribosomal protein S12 generates a phenotype of developmental delay and bang sensitivity. tko(25t) has been intensively studied as an animal model for human mitochondrial diseases ... Transgenic expression in Drosophila of the alternative oxidase (AOX) derived from Ciona intestinalis has previously been shown to mitigate the toxicity of respiratory chain inhibitors and to rescue mutant and knockdown phenotypes ... We therefore tested whether AOX expression could compensate the mutant phenotype of tko(25t) ... We conclude that AOX does not rescue tko(25t) and that the mutant phenotype is not solely due to limitations on electron flow in the respiratory chain, but rather to a more complex metabolic defect. The future therapeutic use of AOX in disorders of mitochondrial translation may thus be of limited value."

Studies use multiple fly models to investigate links between iron and A-beta

Ott S, Dziadulewicz N, Crowther DC. Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms. Dis Model Mech. 2015 Apr 23. pii: dmm.019042. PMID: 26035384.

From the abstract: "Metals including iron are present at high concentrations in amyloid plaques in patients with Alzheimer's disease where they are also thought to be co-factors in generating oxidative stress and modulating amyloid formation. In this study we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and Aβ is specific and is not seen for other aggregation-prone polypeptides. ... Understanding how Aβ mediates neurotoxic effects in vivo will help us better target pathological pathways using aggregation-blockers and metal-modifying agents."

Review looks at contributions of Drosophila research related to Fragile X syndrome and discusses discordance

Weisz ED, Monyak RE, Jongens TA. Deciphering Discord: How Drosophila research has enhanced our understanding of the importance of FMRP in different spatial and temporal contexts. Exp Neurol. 2015 May 27. pii: S0014-4886(15)30001-7. PMID: 26026973.

From the abstract: "Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. ... Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatial and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients."

New fly model related to mitochondrial diseases

Holmbeck MA, Donner JR, Villa-Cuesta E, Rand DM. A Drosophila model for mito-nuclear diseases generated by an incompatible tRNA-tRNA synthetase interaction. Dis Model Mech. 2015 May 5. pii: dmm.019323. PMID: 26035388.

From the abstract: "... Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function."

Fly study related to Parkinson's disease places Clu in context of PINK1, Parkin and mitochondrial quality control

Sen A, Kalvakuri S, Bodmer R, Cox RT. Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila. Dis Model Mech. 2015 Jun 1;8(6):577-589. PMID: 26035866.

From the abstract: "Loss of mitochondrial function often leads to neurodegeneration and is thought to be one of the underlying causes ... we show that clu also genetically interacts with PINK1, and our epistasis analysis places clu downstream of PINK1 and upstream of park. ... Clu forms a complex with PINK1 and Park ... Lack of Clu causes PINK1 and Park to interact with each other, and clu mutants have decreased mitochondrial protein levels ... these results suggest that Clu directly modulates mitochondrial function, and that Clu's function contributes to the PINK1-Park pathway of mitochondrial quality control."

Note:  clu has been conserved--the orthologous human protein appears to be CLUH.

Review--modeling Alzheimers disease in flies

Fernandez-Funez P, de Mena L, Rincon-Limas DE. Modeling the complex pathology of Alzheimer's disease in Drosophila. Exp Neurol. 2015 May 27. pii: S0014-4886(15)00169-7. PMID: 26024860.

New fly model related to Adult T-cell leukemia/lymphoma (ATLL)

Shirinian M, Kambris Z, Hamadeh L, Grabbe C, Journo C, Mahieux R, Bazarbachi A. A transgenic Drosophila melanogaster model to study Human T-Lymphotropic Virus oncoprotein Tax-1-driven transformation in vivo. J Virol. 2015 May 20. pii: JVI.00918-15. PMID: 25995252.

From the abstract: "HTLV-1-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. ... We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. ... Tax-1 but not Tax-2 induces ommatidia perturbation and increased plasmatocyte proliferation ... validating this new in vivo model."

Fly study suggest links between mitochondrial iron transport and Friedreich's ataxia

Navarro JA, Botella JA, Metzendorf C, Lind MI, Schneuwly S. Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich׳s ataxia. Free Radic Biol Med. 2015 Apr 2. pii: S0891-5849(15)00126-4. PMID: 25841783.

From the abstract: "Friedreich׳s ataxia is the most important recessive ataxia in the Caucasian population. Loss of frataxin expression affects the production of iron-sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive iron. ... frataxin-deficient flies were hypersensitive toward dietary iron and developed an iron-dependent decay of mitochondrial functions. ... mitoferrin downregulation improved many of the frataxin-deficient conditions ... whereas mitoferrin overexpression exacerbated most of them. ... demonstrates the crucial role of mitoferrin dysfunction in the etiology of Friedreich׳s ataxia and provides evidence that impairment of mitochondrial iron transport could be an effective treatment of the disease."

Review--flies, iron and neurodegenerative diseases

Zhu ZJ, Wu KC, Qian ZM, Yung WH, Ke Y. Drosophila models for studying iron-related neurodegenerative diseases. Sheng Li Xue Bao. 2014 Feb 25;66(1):47-54. PMID: 24553869.

From the abstract: "In recent years, iron has been regarded as a common pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Friedreich's ataxia (FRDA). ...  characteristics ... turn Drosophila into an excellent in vivo genetic system for screening iron-related modifiers in different neurodegenerative conditions ... "

Review looks at fly and mouse models of Fragile X syndrome

Santos AR, Kanellopoulos AK, Bagni C. Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us. Learn Mem. 2014 Sep 16;21(10):543-55. PMID: 25227249; PMCID: PMC4175497.

From the abstract: "... Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities. "

Fly study related to ALS points to possible new direction for therapeutic development

Chang JC, Hazelett DJ, Stewart JA, Morton DB. Motor neuron expression of the voltage-gated calcium channel cacophony restores locomotion defects in a Drosophila, TDP-43 loss of function model of ALS. Brain Res. 2014 Oct 10;1584:39-51. PMID: 24275199; PMCID: PMC4031311.

From the abstract: "Dysfunction of the RNA-binding protein, TDP-43, is strongly implicated as a causative event in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). ... Using Drosophila melanogaster to model TDP-43 loss of function, we show that reduced levels of the voltage-gated calcium channel, cacophony, mediate some of the physiological effects of TDP-43 loss. ... Restoring the levels of cacophony in all neurons or selectively in motor neurons rescued these locomotion defects. ... If similar effects of cacophony or related calcium channels are found in human ALS patients, these could be targets for the development of pharmacological therapies for ALS."