Drosophila model of Alexander disease used to identify cholinergic signaling as potential therapeutic target

Wang L, Hagemann TL, Messing A, Feany MB. An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci. 2016 Feb 3;36(5):1445-55. PMID: 26843629; PMCID: PMC4737762.

From the abstract: "... Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."

Wondering what is Alexander disease? Read about this rare nervous system disease at NIH Genetics Home Reference.

Detailed phenotypic analysis of flies lacking activity of Nf1, which is associated with neurofibromatosis

King LB, Koch M, Murphy K, Velazquez Y, Ja WW, Tomchik SM. Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila. G3 (Bethesda). 2016 Feb 19. PMID: 26896440.

From the abstract: "Neurofibromatosis I is a common genetic disorder that results in tumor formation and predisposes individuals to a range of cognitive/behavioral symptoms, including deficits in attention, visuospatial skills, learning, language development, sleep, and autism spectrum disorder-like traits. ... Drosophila provide a powerful platform to investigate the signaling cascades upstream and downstream of Nf1, and the fly model exhibits similar behavioral phenotypes to mammalian models. In order to understand how loss of Nf1 affects motor behavior in flies, we combined traditional activity monitoring with video analysis of grooming behavior. In nf1 mutants, spontaneous grooming was increased up to 7x. ... Overall, these data suggest that loss of nf1 produces excessive activity that is manifested as increased grooming, providing a platform to dissect the molecular genetics of neurofibromin signaling across neuronal circuits."

Cutting-edge techniques used in Drosophila help elucidate mechanisms of amphetamine transport in cells

Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, Pizzo AB, Zhang Y, Farino ZJ, Chen A, Martin CA, Kopajtic TA, Fei H, Hu G, Lin YY, Mosharov EV, McCabe BD, Freyberg R, Wimalasena K, Hsin LW, Sames D, Krantz DE, Katz JL, Sulzer D, Javitch JA. Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun. 2016 Feb 16;7:10652. PMID: 26879809.

From the abstract: "Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration ... To study VMAT's role .. we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. ... we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects."

New double-mutant fly model of Adrenoleukodystrophy (ALD) "best paradigm to date"

Sivachenko A, Gordon HB, Kimball SS, Gavin EJ, Bonkowsky JL, Letsou A. Neurodegeneration in a Drosophila model of Adrenoleukodystrophy: the roles of the bubblegum and double bubble acyl-CoA synthetases. Dis Model Mech. 2016 Feb 18. pii: dmm.022244. PMID: 26893370.

From the abstract: "Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders ... novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants ... We show that the Drosophila bubblegum (bgm) and double bubble (dbb) genes have overlapping functions, and that the consequences of ... double knockout in the fly brain are profound ... providing the best paradigm to date for an animal model of Adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very long chain fatty acids. ... in an extension of our model system to the study of human disease, we describe our identification of a leukodystrophy patient who harbors a rare mutation in a human homologue of Bgm and Dbb: the SLC27a6-encoded very-long-chain acyl-CoA synthetase."

New fly model -- fly eye used to study viral-induced cancers

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 Aug;89(15):8092-5. PMID: 25995252; PMCID: PMC4505646.

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.

Tests in fly help shed light on mechanisms relevant to muscular dystrophy

Dialynas G, Shrestha OK, Ponce JM, Zwerger M, Thiemann DA, Young GH, Moore SA, Yu L, Lammerding J, Wallrath LL. Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway. PLoS Genet. 2015 May 21;11(5):e1005231. PMID: 25996830; PMCID: PMC4440730.

From the abstract: "Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand the pathogenesis caused by mutant lamins, we performed a structural and functional analysis on LMNA missense mutations identified in muscular dystrophy patients. These mutations perturb the tertiary structure of the conserved A-type lamin Ig-fold domain. To identify the effects of these structural perturbations on lamin function, we modeled these mutations in Drosophila Lamin C and expressed the mutant lamins in muscle. ... Affected muscles had cytoplasmic aggregation of lamins and additional nuclear envelope proteins. Transcription profiling revealed upregulation of many Nrf2 target genes. ... Elevated p62/SQSTM1 and nuclear enrichment of Nrf2 were identified in muscle biopsies from the corresponding muscular dystrophy patients, validating the disease relevance of our Drosophila model. Thus, novel connections were made between mutant lamins and the Nrf2 signaling pathway, suggesting new avenues of therapeutic intervention that include regulation of protein folding and metabolism, as well as maintenance of redox homoeostasis."

New fly model of SMA type 6

Tsou WL, Hosking RR, Burr AA, Sutton JR, Ouyang M, Du X, Gomez CM, Todi SV. DnaJ-1 and karyopherin α3 suppress degeneration in a new Drosophila model of Spinocerebellar Ataxia Type 6. Hum Mol Genet. 2015 Aug 1;24(15):4385-96. PMID: 25954029; PMCID: PMC4492400.

Flies and sleep and neuronal diseases -- review

Zordan MA, Sandrelli F. Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say? Front Neurol. 2015 Apr 20;6:80. PMID: 25941512; PMCID: PMC4403521.

From the abstract: "There is evidence of a link between the circadian system and psychiatric diseases. ... Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. ... We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease."

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.

Review discusses fly as model for studying chromatin factors relevant to intellectual disability

Looks like a nice starting point or resource for someone interested to use the fly to study chromatin regulators and neurological diseases.

Taniguchi H, Moore AW. Chromatin regulators in neurodevelopment and disease: Analysis of fly neural circuits provides insights: Networks of chromatin regulators and transcription factors underlie Drosophila neurogenesis and cognitive defects in intellectual disability and neuropsychiatric disorder models. Bioessays. 2014 Sep;36(9):872-83. PMID: 25067789.

From the abstract:  "Disruptions in chromatin regulator genes are frequently the cause of neurodevelopmental and neuropsychiatric disorders. ... Using Drosophila allows targeted manipulation of chromatin regulators in defined neuronal classes, lineages, or circuits, revealing their roles in neuronal precursor self-renewal, dendrite and axon targeting, neuron diversification, and the tuning of developmental signaling pathways. ..."

Review discusses fly and other models of heart failure

Kooij V, Venkatraman V, Tra J, Kirk JA, Rowell J, Blice-Baum A, Cammarato A, Van Eyk JE. Sizing up models of heart failure: Proteomics from flies to humans. Proteomics Clin Appl. 2014 Oct;8(9-10):653-64. PMID: 24723306; PMCID: PMC4282793.

From the abstract: "Cardiovascular disease is the leading cause of death in the western world. Heart failure is a heterogeneous and complex syndrome... The ability to utilize genetic manipulation and biochemical experimentation in animal models has made them indispensable ... Similarly, proteomics has been helpful for elucidating complicated cellular and molecular phenotypes and has the potential to identify circulating biomarkers and drug targets ... In this review, the use of human samples and animal model systems (pig, dog, rat, mouse, zebrafish, and fruit fly) in cardiac research is discussed. Additionally, the protein sequence homology between these species and the extent of conservation at the level of the phospho-proteome in major kinase signaling cascades involved in heart failure are investigated."

Results of Drosophila study might shed light on tumor predisposition in X-linked dyskeratosis

Vicidomini R, Di Giovanni A, Petrizzo A, Iannucci LF, Benvenuto G, Nagel AC, Preiss A, Furia M. Loss of Drosophila pseudouridine synthase triggers apoptosis-induced proliferation and promotes cell-nonautonomous EMT. Cell Death Dis. 2015 Mar 26;6:e1705. PMID: 25811802; PMCID: PMC4385944.

From the abstract: "Many developing tissues display regenerative capability that allows them to compensate cell loss and preserve tissue homeostasis. Because of their remarkable regenerative capability, Drosophila wing discs are extensively used for the study of regenerative phenomena. We thus used the developing wing to investigate the role played in tissue homeostasis by the evolutionarily conserved eukaryotic H/ACA small nucleolar ribonucleoprotein pseudouridine synthase. Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells. In fact, some cells undergo apoptosis, whereas those surrounding the apoptotic foci, although identically depleted, overproliferate. ... Collectively, these data point out that cell-cell communication and long-range signaling can take a relevant role in the response to pseudouridine synthase decline. Considering that all the affected pathways are highly conserved throughout evolution, it is plausible that the response to pseudouridine synthase depletion has been widely preserved. On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity."

Fly study suggests link between bisphenol A (BPA), found in some plastics, and ADHD and autism

The results suggest BPA is a risk factor for the behavioral impairments that are the basis of autism and ADHD https://t.co/xzhUxws8ql

— Thomas Brody (@interactivefly) February 15, 2016

FlyRNAi: Cultured Drosophila cells 'humanized' for drug stu...

FlyRNAi: Cultured Drosophila cells 'humanized' for drug stu...: Generating a "Humanized" Drosophila S2 Cell Line Sensitive to Pharmacological Inhibition of Kinesin-5. https://t.co/Cykmii1hlq — f...