Cross-species analysis related to Huntington's disease (fly, mouse, human)

Elife. 2021 Apr 19;10:e64564. doi: 10.7554/eLife.64564. Online ahead of print.

Downregulation of glial genes involved in synaptic function mitigates Huntington's Disease pathogenesis.

Onur TS, Laitman A, Zhao H, Keyho R, Kim H, Wang J, Mair M, Wang H, Li L, Perez A, de Haro M, Wan YW, Allen G, Lu B, Al-Ramahi I, Liu Z, Botas J

Abstract:

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the  excitotoxicity that characterizes HD.

DOI: 10.7554/eLife.64564
PMID: 33871358

'Multilayered' approach to study of Huntington Disease includes testing in fly HD models

Al-Ramahi I, Lu B, Di Paola S, Pang K, de Haro M, Peluso I, Gallego-Flores T, Malik NT, Erikson K, Bleiberg BA, Avalos M, Fan G, Rivers LE, Laitman AM, Diaz-García JR, Hild M, Palacino J, Liu Z, Medina DL, Botas J. High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration. Cell Syst. 2018 Jul 25;7(1):28-40.e4. PubMed PMID: 29936182; PubMed Central PMCID: PMC6082401.

Abstract: "Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points."

Flies used to test drug activity predicted using dynamic combinatorial chemistry approach

Canal-Martín A, Sastre J, Sánchez-Barrena MJ, Canales A, Baldominos S, Pascual N, Martínez-González L, Molero D, Fernández-Valle ME, Sáez E, Blanco-Gabella P, Gómez-Rubio E, Martín-Santamaría S, Sáiz A, Mansilla A, Cañada FJ, Jiménez-Barbero J, Martínez A, Pérez-Fernández R. Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library. Nat Commun. 2019 Jun 26;10(1):2798. PMID: 31243268; PMCID: PMC6595003.

Abstract: "Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations."

Reports related to neurodegenerative and neuromuscular disorders

Bondar VV, Adamski CJ, Onur TS, Tan Q, Wang L, Diaz-Garcia J, Park J, Orr HT, Botas J, Zoghbi HY. PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in spinocerebellar ataxia type 1. Hum Mol Genet. 2018 Aug 15;27(16):2863-2873.PMID: 29860311; PMCID: PMC6077814.

From the abstract: "... Loss-of-function of fly Pak3 or Pak1, whose mammalian homologs belong to Group I of PAK proteins, reduces ATXN1 levels, and accordingly, improves disease pathology in a Drosophila model of SCA1. Knockdown of PAK1 potently reduces ATXN1 levels in mammalian cells ... this study identifies PAK signaling as a distinct molecular pathway that regulates ATXN1 levels and presents a promising opportunity to pursue for developing potential therapeutics for SCA1."

Adusumalli S, Ngian ZK, Lin WQ, Benoukraf T, Ong CT. Increased intron retention is a post-transcriptional signature associated with progressive aging and Alzheimer's disease. Aging Cell. 2019 Mar 13:e12928. PMID: 30868713.

From the abstract: "Intron retention (IR) by alternative splicing is a conserved regulatory mechanism that can affect gene expression and protein function during adult development and age-onset diseases. ... By profiling the transcriptome of Drosophila head cells at different ages, we observed a significant increase in IR events for many genes during aging. ... our results suggest that an increased IR is an conserved signature that is associated with aging. ... changes of IR pattern during aging may regulate the transition from healthy to pathological state in late-onset sporadic AD."

Wang TH, Wang SY, Wang XD, Jiang HQ, Yang YQ, Wang Y, Cheng JL, Zhang CT, Liang WW, Feng HL. Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK. Neuroscience. 2018 May 21;379:152-166. PMID: 29559385.

From the abstract: "Oxidative stress exhibits a central role in the course of amyotrophic lateral sclerosis (ALS) ... Fisetin, a natural antioxidant, has shown benefits in varied neurodegenerative diseases. ... Three different hSOD1-related mutant models were used ... results indicate that fisetin protects cells from ROS damage and improves the pathological behaviors caused by oxidative stress in disease models related to SOD1 gene mutations ... providing a potential treatment for ALS."

Lakkappa N, Krishnamurthy PT, M D P, Hammock BD, Hwang SH. Soluble epoxide hydrolase inhibitor, APAU, protects dopaminergic neurons against rotenone induced neurotoxicity: Implications for Parkinson's disease. Neurotoxicology. 2019 Jan;70:135-145. PMID: 30472438.

From the abstract: "Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inflammation and apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel strategy for neuroprotection. ... sEH inhibitors APAU was screened in silico and further evaluated for their antiparkinson activity against rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and Drosophila melanogaster model of Parkinson disease (PD). ..."

 Krench M, Cho RW, Littleton JT. A Drosophila model of Huntington disease-like 2 exhibits nuclear toxicity and distinct pathogenic mechanisms from Huntington disease. Hum Mol Genet. 2016 Aug 1;25(15):3164-3177. PMID: 27288455; PMCID: PMC5179919.

From the abstract: "Huntington disease-like 2 (HDL2) and Huntington disease (HD) are adult-onset neurodegenerative diseases ... we generated and characterized a Drosophila HDL2 model and compared it with a previously established HD model. We find that neuronal expression of HDL2-Q15 is not toxic, while the expression of an expanded HDL2-Q138 protein is lethal. HDL2-Q138 forms large nuclear aggregates, with only smaller puncta observed in the cytoplasm. This is in contrast to what is observed in a Drosophila model of HD, where polyQ aggregates localize exclusively to the cytoplasm. ... We conclude that while HD and HDL2 have similar clinical profiles, distinct pathogenic mechanisms are likely to drive toxicity in Drosophila models of these disorders."

Poska H, Haslbeck M, Kurudenkandy FR, Hermansson E, Chen G, Kostallas G, Abelein A, Biverstål H, Crux S, Fisahn A, Presto J, Johansson J. Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila. Biochem J. 2016 Oct 15;473(20):3683-3704. PMID: 27514716.

From the abstract: "Formation of fibrils of the amyloid-β peptide (Aβ) is suggested to play a central role in neurodegeneration in Alzheimer's disease (AD), for which no effective treatment exists. The BRICHOS domain is a part of several disease-related proproteins ... we find that transgenic expression of the Bri2 BRICHOS domain in the Drosophila central nervous system (CNS) or eyes efficiently inhibits Aβ42 toxicity. ... These findings suggest that Bri2 BRICHOS can be a physiologically relevant chaperone for Aβ in the CNS ..."

FRET-based assay related to Huntington's disease tested in mouse and fly models

Ast A, Buntru A, Schindler F, Hasenkopf R, Schulz A, Brusendorf L, Klockmeier K, Grelle G, McMahon B, Niederlechner H, Jansen I, Diez L, Edel J, Boeddrich A, Franklin SA, Baldo B, Schnoegl S, Kunz S, Purfürst B, Gaertner A, Kampinga HH, Morton AJ, Petersén Å, Kirstein J, Bates GP, Wanker EE. mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease. Mol Cell. 2018 Sep 6;71(5):675-688.e6. PMID: 30193095.

From the abstract: "Self-propagating, amyloidogenic mutant huntingtin (mHTT) aggregates may drive progression of Huntington's disease (HD). Here, we report the development of a FRET-based mHTT aggregate seeding (FRASE) assay that enables the quantification of mHTT seeding activity (HSA) ... Application of the FRASE assay revealed HSA in brain homogenates of presymptomatic HD transgenic and knockin mice and its progressive increase with phenotypic changes, suggesting that HSA quantitatively tracks disease progression. Biochemical investigations ... demonstrated that small, rather than large, mHTT structures are responsible for the HSA measured in FRASE assays. Finally, we assessed the neurotoxicity of mHTT seeds in an inducible Drosophila model transgenic for HTTex1. We found a strong correlation between the HSA measured in adult neurons and the increased mortality of transgenic HD flies, indicating that FRASE assays detect disease-relevant, neurotoxic, mHTT structures with severe phenotypic consequences in vivo."

Preprint: New fly model of SeSAME syndrome

Posted December 2018 on the preprint server:

Ravi K Nadella, Anirudh Chellappa, Anand G Subramaniam, View ORCID ProfileAman Aggarwal, Ravi Prabhakar More, Mahalakshmi Dhana sekar, Srividya Shetty, Suriya Prakash, Nikhil Ratna, Vandana VP, Meera Purushotham, Jitender Saini, Biju Viswanath, Bindu PS, Madhu Nagappa, Bhupesh Mehta, Sanjeev Jain, View ORCID ProfileRamakrishnan Kannan

Novel KCNJ10 mutation identified in a SeSAME family compromise channel function and impairs Drosophila locomotor behavior
https://www.biorxiv.org/content/10.1101/506949v1

From the preprint abstract: "Deficits in the inwardly rectifying K channel, Kir4.1, cause SeSAME syndrome, autism spectrum disorders with seizures, multiple sclerosis, Huntington disease and Rett syndrome. ... We used whole exome sequencing (WES), channel physiology in patient-specific lymphoblastoid cells (LCLs) and established a Drosophila model to examine the functional effects of a KCNJ10 variant identified in SeSAME like family. ... Drosophila irk2 mutant, a human homolog of Kir4.1, exhibited impairment locomotion, shortened life span and age dependent degeneration of dopaminergic neurons in the adult brain. ... neural specific expression of either Kir4.1 or Irk2 alleviate irk2 mutant phenotypes, while the Kir4.1(T290A) and Irk2(T290A) mutant proteins failed to do so. These results imply the functional conservation of Kir4.1 across species thereby elevate the potential of using Drosophila model to improve our understanding of the SeSAME syndrome. ..."

Expression of human disease alleles in Drosophila used to study cellular mechanisms of diseases associated with polyglutamine expansion

Vu A, Humphries T, Vogel S, Haberman A. Polyglutamine repeat proteins disrupt actin structure in Drosophila photoreceptors. Mol Cell Neurosci. 2018 Aug 24. PMID: 30149064.

The abstract: "Expansions of polygutamine-encoding stretches in several genes cause neurodegenerative disorders including Huntington's Disease and Spinocerebellar Ataxia type 3. Expression of the human disease alleles in Drosophila melanogaster neurons recapitulates cellular features of these disorders, and has therefore been used to model the cell biology of these diseases. Here, we show that polyglutamine disease alleles expressed in Drosophila photoreceptors disrupt actin structure at rhabdomeres, as other groups have shown they do in Drosophila and mammalian dendrites. We show this actin regulatory pathway works through the small G protein Rac and the actin nucleating protein Form3. We also find that Form3 has additional functions in photoreceptors, and that loss of Form3 results in the specification of extra photoreceptors in the eye."

Review of fly research in the area of Huntington's Disease

Rosas-Arellano A, Estrada-Mondragón A, Piña R, Mantellero CA, Castro MA. The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington's Disease. Int J Mol Sci. 2018 Aug 14;19(8). PMID: 30110961.

The abstract: "The average life expectancy for humans has increased over the last years. However, the quality of the later stages of life is low and is considered a public health issue of global importance. Late adulthood and the transition into the later stage of life occasionally leads to neurodegenerative diseases that selectively affect different types of neurons and brain regions, producing motor dysfunctions, cognitive impairment, and psychiatric disorders that are progressive, irreversible, without remission periods, and incurable. Huntington's disease (HD) is a common neurodegenerative disorder. In the 25 years since the mutation of the huntingtin (HTT) gene was identified as the molecule responsible for this neural disorder, a variety of animal models, including the fruit fly, have been used to study the disease. Here, we review recent research that used Drosophila as an experimental tool for improving knowledge about the molecular and cellular mechanisms underpinning HD."

Metabolic study in a Drosophila model of Huntington Disease

Sameni S, Syed A, Marsh JL, Digman MA. The phasor-FLIM fingerprints reveal shifts from OXPHOS to enhanced glycolysis in Huntington Disease. Sci Rep. 2016 Oct 7;6:34755. doi: 10.1038/srep34755. PubMed PMID: 27713486; PubMed Central PMCID: PMC5054433.

From the abstract: "Huntington disease (HD) is an autosomal neurodegenerative disorder ... Impairment in energy metabolism is a common trend in Huntington pathogenesis ... Here, we used the phasor approach and Fluorescence Lifetime Imaging Microscopy (FLIM) to measure changes between free and bound fractions of NADH as a indirect measure of metabolic alteration in living cells. Using Phasor-FLIM, pixel maps of metabolic alteration in HEK293 cell lines and in transgenic Drosophila expressing expanded and unexpanded polyQ HTT exon1 in the eye disc were developed. We found a significant shift towards increased free NADH, indicating an increased glycolytic state for cells and tissues expressing the expanded polyQ compared to unexpanded control. In the nucleus, a further lifetime shift occurs towards higher free NADH suggesting a possible synergism between metabolic dysfunction and transcriptional regulation. Our results indicate that metabolic dysfunction in HD shifts to increased glycolysis leading to oxidative stress and cell death. This powerful label free method can be used to screen native HD tissue samples and for potential drug screening."

Investigation of the effects of green tea on a fly model of Huntington's Disease

Varga J, Dér NP, Zsindely N, Bodai L. Green tea infusion alleviates neurodegeneration induced by mutant Huntingtin in Drosophila. Nutr Neurosci. 2018 Jul 4:1-7. PMID: 29973113.

From the abstract: "Green tea infusion contains a complex mixture of polyphenolic compounds that were shown to provide health benefits. It was previously demonstrated that (-)-epigallocatechin-3-gallate, ... present in green tea, has a suppressing effect on various aspects of pathogenesis in models of Huntington's disease (HD) ... In this study, we aimed to investigate, whether green tea infusion prepared as for human consumption has similar positive effects. ... We used a transgenic Drosophila model of HD to study the effects of green tea on mutant Huntingtin induced phenotypes. ... We found that green tea supplementation reduced mutant Huntingtin induced neurodegeneration in Drosophila and positively impacted the longevity of mutant Huntingtin expressing flies. However, green tea did not rescue reduced viability of Drosophila expressing mutant Huntingtin or increased longevity of wild-type fruit flies. ... Our results indicate that green tea consumption might have a modest positive effect on symptoms of HD."

Fly studies used to gain functional understanding of changes associated with Huntington's disease

Al-Ramahi I, Lu B, Di Paola S, Pang K, de Haro M, Peluso I, Gallego-Flores T, Malik NT, Erikson K, Bleiberg BA, Avalos M, Fan G, Rivers LE, Laitman AM, Diaz-García JR, Hild M, Palacino J, Liu Z, Medina DL, Botas J. High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration. Cell Syst. 2018 Jun 6. pii: S2405-4712(18)30228-X. PMID: 29936182.

From the abstract: "Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. ... Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points."

Fly model of neurodegeneration used in study of glycation

Vicente Miranda H, Gomes MA, Branco-Santos J, Breda C, Lázaro DF, Lopes LV, Herrera F, Giorgini F, Outeiro TF. Glycation potentiates neurodegeneration in models of Huntington's disease. Sci Rep. 2016 Nov 18;6:36798. PMID: 27857176; PMCID: PMC5114697.

From the abstract: "Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). ... increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity ...."

Metal-related diseases studied using Drosophila

Calap-Quintana P, González-Fernández J, Sebastiá-Ortega N, Llorens JV, Moltó MD. Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity. Int J Mol Sci. 2017 Jul 6;18(7). pii: E1456. PMID: 28684721.

From the abstract: "Iron, copper and zinc are transition metals essential for life ... Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. ... many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. ... This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided."

Fly as whole-animal petri dish: exploring pathogenesis related to Huntington's disease

Barbaro BA, Lukacsovich T, Agrawal N, Burke J, Bornemann DJ, Purcell JM, Worthge SA, Caricasole A, Weiss A, Song W, Morozova OA, Colby DW, Marsh JL. Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. Hum Mol Genet. 2015 Feb 15;24(4):913-25. PMID: 25305076; PMCID: PMC4834878.

From the abstract: "Although Huntington's disease is caused by the expansion of a CAG triplet repeat within the context of the 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments of HTT containing the expanded PolyQ region can be produced by proteolytic processing and/or aberrant splicing. N-terminal HTT fragments are also prevalent in postmortem tissue, and expression of some of these fragments in model organisms can cause pathology. This has led to the hypothesis that N-terminal peptides may be critical modulators of disease pathology, raising the possibility that targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets. ... We have used Drosophila as a model system to determine the relative toxicities of different naturally occurring huntingtin fragments in a system in which genetic background, transgene expression levels and post-translational proteolytic processing can be controlled. ... If this proves correct, efforts to specifically reduce the levels of exon 1 peptides or to target toxicity-influencing post-translational modifications that occur with the exon 1 context are likely to have the greatest impact on pathology."

Green-glowing flies used in study relevant to Huntington's disease

Babcock DT, Ganetzky B. Transcellular spreading of huntingtin aggregates in the Drosophila brain. Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):E5427-33. PMID: 26351672; PMCID: PMC4593132.

From the abstract: "A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease. ... We show that Htt aggregates cause non-cell-autonomous pathology ..."

Catching up (or at least, beginning to) on neurodegenerative disease-related fly papers

Reviews

Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol. 2015 Jun;63:60-5. PMID: 25666557.

Repalli J. Translocator protein (TSPO) role in aging and Alzheimer's disease. Curr Aging Sci. 2014;7(3):168-75. PMID: 25495567; PMCID: PMC4435228.

Research papers

Wu K, Liu J, Zhuang N, Wang T. UCP4A protects against mitochondrial dysfunction and degeneration in pink1/parkin models of Parkinson's disease. FASEB J. 2014 Dec;28(12):5111-21. PMID: 25145627.

Vorobyeva AG, Lee R, Miller S, Longen C, Sharoni M, Kandelwal PJ, Kim FJ, Marenda DR, Saunders AJ. Cyclopamine modulates γ-secretase-mediated cleavage of amyloid precursor protein by altering its subcellular trafficking and lysosomal degradation. J Biol Chem. 2014 Nov 28;289(48):33258-74. PMID: 25281744; PMCID: PMC4246084.

Butzlaff M, Hannan SB, Karsten P, Lenz S, Ng J, Voßfeldt H, Prüßing K, Pflanz R, Schulz JB, Rasse T, Voigt A. Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity. Hum Mol Genet. 2015 Jul 1;24(13):3623-37. PMID: 25794683.

Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, Gonzalez MA, Scott 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. ---See also comment and reply.

Doll CA, Broadie K. Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory. Development. 2015 Apr 1;142(7):1346-56. PMID: 25804740; PMCID: PMC4378248.

Sanhueza M, Chai A, Smith C, McCray BA, Simpson TI, Taylor JP, Pennetta G. Network analyses reveal novel aspects of ALS pathogenesis. PLoS Genet. 2015 Mar 31;11(3):e1005107. PMID: 25826266; PMCID: PMC4380362.

Dalui S, Bhattacharyya A. Herbicide paraquat induces sex-specific variation of neuroinflammation and neurodegeneration in Drosophila melanogaster. Indian J Biochem Biophys. 2014 Dec;51(6):567-73. PubMed PMID: 25823231.

Jimenez-Sanchez M, Lam W, Hannus M, Sönnichsen B, Imarisio S, Fleming A, Tarditi A, Menzies F, Ed Dami T, Xu C, Gonzalez-Couto E, Lazzeroni G, Heitz F, Diamanti D, Massai L, Satagopam VP, Marconi G, Caramelli C, Nencini A, Andreini
M, Sardone GL, Caradonna NP, Porcari V, Scali C, Schneider R, Pollio G, O'Kane CJ, Caricasole A, Rubinsztein DC. siRNA screen identifies QPCT as a draggable target for Huntington's disease. Nat Chem Biol. 2015 May;11(5):347-54. PMID: 25848931; PMCID: PMC4696152.

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.

Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, Lin S, Shneider NA, Monaghan J, Pandey UB, Pasinelli P, Ichida JK, Trotti D. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron. 2014 Dec 17;84(6):1213-25. PMID: 25521377; PMCID: PMC4632245.

Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh JL, Housman DE, Thompson LM, Steffan JS. Potential function for the Huntington protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16889-94. PMID: 25385587; PMCID: PMC4250109.

Wade AR, Elliott CJ. Could the detection of visual disturbances associated with Parkinson's disease genes in flies lead to new treatments for the disease? Neurodegener Dis Manag. 2014;4(4):291-3. PMID: 25313984.

Yin G, Lopes da Fonseca T, Eisbach SE, Anduaga AM, Breda C, Orcellet ML, Szegő ÉM, Guerreiro P, Lázaro DF, Braus GH, Fernandez CO, Griesinger C, Becker S, Goody RS, Itzen A, Giorgini F, Outeiro TF, Zweckstetter M. α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiol Dis. 2014 Oct;70:149-61. PMID: 24983211.

Kim Y, Park H, Nah J, Moon S, Lee W, Hong SH, Kam TI, Jung YK. Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition. Biochem Biophys Res Commun. 2015 Jun 26;462(2):112-8. PMID: 25930997.

Scaramuzzino C, Casci I, Parodi S, Lievens PM, Polanco MJ, Milioto C, Chivet M, Monaghan J, Mishra A, Badders N, Aggarwal T, Grunseich C, Sambataro F, Basso M, Fackelmayer FO, Taylor JP, Pandey UB, Pennuto M. Protein arginine
methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy. Neuron. 2015 Jan 7;85(1):88-100. PMID: 25569348; PMCID: PMC4305189.

Huntingtin protein as a scaffold for macroautophagy

Rui YN, Xu Z, Patel B, Chen Z, Chen D, Tito A, David G, Sun Y, Stimming EF, Bellen HJ, Cuervo AM, Zhang S. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015 Mar;17(3):262-75. PMID: 25686248; PMCID: PMC4344873.

From the abstract: "Selective macroautophagy is an important protective mechanism against diverse cellular stresses. ... Here, we demonstrate that Huntingtin, the Huntington disease gene product, functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy. In Drosophila, Huntingtin genetically interacts with autophagy pathway components. In mammalian cells, Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates. ... Our data uncover an important physiological function of Huntingtin and provide a missing link in the activation of selective macroautophagy in metazoans."

See also comment in:
Gelman A, Rawet-Slobodkin M, Elazar Z. Huntingtin facilitates selective autophagy. Nat Cell Biol. 2015 Mar;17(3):214-5. PMID: 25720962.

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 ... "

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.”

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."