Abstract
The fruit fly, Drosophila melanogaster, is an attractive model for studying human disease. The popularity of the model is a consequence of its well-developed toolbox for genetic engineering and the finding that 75% of genes that cause human disease have orthologs in the fly. Diseases of the human nervous system have been modeled extensively in the fly, taking advantage of a complex, well mapped out nervous system. A popular strategy to model a disease is to identify the fly ortholog of a disease gene and develop an experimental model, based on the ortholog, to gain insight into the mechanisms of gene function and malfunction. The lessons learned from the fly can then be used to dissect out the cellular and molecular basis of the disease in humans.
In this chapter, we highlight research using Drosophila to gain insight into mechanisms that underlie neurodegenerative diseases, with a focus on amyotrophic lateral sclerosis (ALS). Till date, 31 familial genetic loci have been identified in ALS, with each gene involved in cellular processes that are widely divergent from each other. This divergence of function has hampered efforts to elucidate a common model for the initiation and progression of ALS. Here we describe well-established fly models for C9ORF72, SOD1, TDP-43, FUS, VAP, and VCP. We explore the alterations in protein and RNA homeostasis, metabolic changes, intracellular and intercellular signaling, and transport, stress, and immune response concerning each of these genetic loci as well as architectural changes that occur during development and aging of the fly. Studies that provide evidence for common themes between these loci through genetic, epistatic, or physical interaction have been highlighted.
Many cellular hallmarks of these diseases can be recapitulated in Drosophila, providing a platform to conduct further sophisticated genetic and chemical perturbations to gain a better understanding of the human disease. In this chapter, we speculate on the possibility of a gene regulatory network that underlies the breakdown in motor function in ALS, composed of ALS causative genes, which reveal critical mechanistic features that can be targeted for therapy.
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Alami, N. H., Smith, R. B., Carrasco, M. A., et al. (2014). Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron, 81, 536–543. https://doi.org/10.1016/j.neuron.2013.12.018.
Altanbyek, V., Cha, S. J., Kang, G. U., et al. (2016). Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis. Biochemical and Biophysical Research Communications, 481, 259–264. https://doi.org/10.1016/j.bbrc.2016.10.134.
Andersen, P. M., & Al-Chalabi, A. (2011). Clinical genetics of amyotrophic lateral sclerosis: What do we really know? Nature Reviews. Neurology, 7, 603–615. https://doi.org/10.1038/nrneurol.2011.150.
Bahadorani, S., Mukai, S. T., Rabie, J., et al. (2013). Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction. Neurobiology of Aging, 34, 2322–2330. https://doi.org/10.1016/j.neurobiolaging.2013.03.024.
Bharadwaj, R., Cunningham, K. M., Zhang, K., & Lloyd, T. E. (2016). FIG 4 regulates lysosome membrane homeostasis independent of phosphatase function. Human Molecular Genetics, 25, 681–692. https://doi.org/10.1093/HMG/DDV505.
Blokhuis, A. M., Groen, E. J. N., Koppers, M., et al. (2013). Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathologica, 125, 777–794. https://doi.org/10.1007/s00401-013-1125-6.
Boeynaems, S., Bogaert, E., Michiels, E., et al. (2016). Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Scientific Reports, 6, 7–14. https://doi.org/10.1038/srep20877.
Bogaert, E., Boeynaems, S., Kato, M., et al. (2018). Molecular dissection of FUS points at synergistic effect of low-complexity domains in toxicity. Cell Reports, 24, 529–537.e4. https://doi.org/10.1016/j.celrep.2018.06.070.
Boillée, S., Vande Velde, C., & Cleveland, D. W. (2006). ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron, 52, 39–59. https://doi.org/10.1016/j.neuron.2006.09.018.
Celona, B., Von Dollen, J., Vatsavayai, S. C., et al. (2017). Suppression of c9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106. eLife, 6, 1–17. https://doi.org/10.7554/eLife.19032.
Chai, A., Withers, J., Koh, Y. H., et al. (2008). hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction. Human Molecular Genetics, 17, 266–280. https://doi.org/10.1093/hmg/ddm303.
Chang, J. C., & Morton, D. B. (2017). Drosophila lines with mutant and wild type human TDP-43 replacing the endogenous gene reveals phosphorylation and ubiquitination in mutant lines in the absence of viability or lifespan defects. PLoS One, 12, 1–24. https://doi.org/10.1371/journal.pone.0180828.
Chang, Y. C., Hung, W. T., Chang, Y. C., et al. (2011). Pathogenic VCP/TER94 alleles are dominant actives and contribute to neurodegeneration by altering cellular ATP level in a drosophila IBMPFD model. PLoS Genetics, 7(2), e1001288. https://doi.org/10.1371/journal.pgen.1001288.
Chaplot, K., Pimpale, L., Ramalingam, B., et al. (2019). SOD1 activity threshold and TOR signalling modulate VAP(P58S) aggregation via reactive oxygen speciesinduced proteasomal degradation in a Drosophila model of amyotrophic lateral sclerosis. Disease Models & Mechanisms, 12, dmm033803. https://doi.org/10.1242/dmm.033803.
Chen, H.-J., Anagnostou, G., Chai, A., et al. (2010). Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. The Journal of Biological Chemistry, 285, 40266–40281. https://doi.org/10.1074/jbc.M110.161398.
Chen, Y., Yang, M., Deng, J., et al. (2011). Expression of human FUS protein in Drosophila leads to progressive neurodegeneration. Protein & Cell, 2, 477–486. https://doi.org/10.1007/s13238-011-1065-7.
Chiriboga, C. A., Swoboda, K. J., Darras, B. T., et al. (2016). Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology, 86, 890–897. https://doi.org/10.1212/WNL.0000000000002445.
Collins, C. A., Wairkar, Y. P., Johnson, S. L., & DiAntonio, A. (2006). Highwire restrains synaptic growth by attenuating a MAP kinase signal. Neuron, 51, 57–69. https://doi.org/10.1016/j.neuron.2006.05.026.
Couthouis, J., Hart, M. P., Shorter, J., et al. (2011). A yeast functional screen predicts new candidate ALS disease genes. Proceedings of the National Academy of Sciences, 108, 20881–20890. https://doi.org/10.1073/pnas.1109434108.
Couthouis, J., Hart, M. P., Erion, R., et al. (2012). Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Human Molecular Genetics, 21, 2899–2911. https://doi.org/10.1093/hmg/dds116.
Coyne, A. N., Siddegowda, B. B., Estes, P. S., et al. (2014). Futsch/MAP 1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. The Journal of Neuroscience, 34, 15962–15974. https://doi.org/10.1523/JNEUROSCI.2526-14.2014.
Cragnaz, L., Klima, R., De Conti, L., et al. (2015). An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience, 311, 415–421. https://doi.org/10.1016/j.neuroscience.2015.10.037.
Crippa, V., Cicardi, M. E., Ramesh, N., et al. (2016). The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity. Human Molecular Genetics, 25, 3908–3924. https://doi.org/10.1093/hmg/ddw232.
Deivasigamani, S., Verma, H. K., Ueda, R., et al. (2014). A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis. Biology Open, 3, 1127–1138. https://doi.org/10.1242/bio.201410066.
Diaper, D. C., Adachi, Y., Lazarou, L., et al. (2013a). Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD. Human Molecular Genetics, 22, 3883–3893. https://doi.org/10.1093/hmg/ddt243.
Diaper, D. C., Adachi, Y., Sutcliffe, B., et al. (2013b). Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes. Human Molecular Genetics, 22, 1539–1557. https://doi.org/10.1093/hmg/ddt005.
Elden, A. C., Kim, H. J., Hart, M. P., et al. (2010). Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature, 466, 1069–1075. https://doi.org/10.1038/nature09320.
Elia, A. J. (1999). Expression of human FALS SOD in motoneurons of Drosophila. Free Radical Biology & Medicine, 26, 1332–1338.
Estes, P. S., Boehringer, A., Zwick, R., et al. (2011). Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Human Molecular Genetics, 20, 2308–2321. https://doi.org/10.1093/hmg/ddr124.
Estes, P. S., Daniel, S. G., Mccallum, A. P., et al. (2013). Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis. Disease Models & Mechanisms, 6, 721–733. https://doi.org/10.1242/dmm.010710.
Feiguin, F., Godena, V. K., Romano, G., et al. (2009). Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Letters, 583, 1586–1592. https://doi.org/10.1016/j.febslet.2009.04.019.
Ferraiuolo, L., Kirby, J., Grierson, A. J., et al. (2011). Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nature Reviews. Neurology, 7, 616–630. https://doi.org/10.1038/nrneurol.2011.152.
Feuillette, S., Delarue, M., Riou, G., et al. (2017). Neuron-to-neuron transfer of FUS in Drosophila primary neuronal culture is enhanced by ALS-associated mutations. Journal of Molecular Neuroscience, 62, 114–122. https://doi.org/10.1007/s12031-017-0908-y.
Forrest, S., Chai, A., Sanhueza, M., et al. (2013). Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis. Human Molecular Genetics, 22, 2689–2704. https://doi.org/10.1093/hmg/ddt118.
Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., et al. (2015). GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature, 525, 129–133. https://doi.org/10.1038/nature14974.
Fujita, K., Nakamura, Y., Oka, T., et al. (2013). A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases. Nature Communications, 4, 1816.
Funke, A. D., Esser, M., Krüttgen, A., et al. (2010). The p.P56S mutation in the VAPB gene is not due to a single founder: The first European case. Clinical Genetics, 77, 302–303. https://doi.org/10.1111/j.1399-0004.2009.01319.x.
Ganguly, A. A., Feldman, R. R. M., & Guo, M. (2008). Ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila. Human Molecular Genetics, 17, 293–302. https://doi.org/10.1093/hmg/ddm305.
Gregory, J. M., Barros, T. P., Meehan, S., et al. (2012). The aggregation and neurotoxicity of TDP-43 and its als-associated 25 kDa fragment are differentially affected by molecular chaperones in drosophila. PLoS One, 7, e31899. https://doi.org/10.1371/journal.pone.0031899.
Gregory, J. M., Whiten, D. R., Brown, R. A., et al. (2017). Clusterin protects neurons against intracellular proteotoxicity. Acta Neuropathologica Communications, 5, 81. https://doi.org/10.1186/s40478-017-0481-1.
Griciuc, A., Aron, L., Piccoli, G., & Ueffing, M. (2010a). Clearance of Rhodopsin(P23H) aggregates requires the ERAD effector VCP. Biochimica et Biophysica Acta, 1803, 424–434. https://doi.org/10.1016/j.bbamcr.2010.01.008.
Griciuc, A., Aron, L., Roux, M. J., et al. (2010b). Inactivation of VCP/ter94 suppresses retinal pathology caused by misfolded rhodopsin in Drosophila. PLoS Genetics, 6(8). https://doi.org/10.1371/journal.pgen.1001075.
Guo, W., Chen, Y., Zhou, X., et al. (2011). An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nature Structural & Molecular Biology, 18, 822–830. https://doi.org/10.1038/nsmb.2053.
Han, S. M., Tsuda, H., Yang, Y., et al. (2012). Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors. Developmental Cell, 22, 348–362. https://doi.org/10.1016/j.devcel.2011.12.009.
Hanson, K. A., Kim, S. H., Wassarman, D. A., & Tibbetts, R. S. (2010). Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). The Journal of Biological Chemistry, 285, 11068–11072. https://doi.org/10.1074/jbc.C109.078527.
Hautbergue, G. M., Castelli, L. M., Ferraiuolo, L., et al. (2017). SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nature Communications, 8, 1–18. https://doi.org/10.1038/ncomms16063.
Hazelett, D. J., Chang, J.-C., Lakeland, D. L., & Morton, D. B. (2012). Comparison of parallel high-throughput RNA sequencing between knockout of TDP-43 and its overexpression reveals primarily nonreciprocal and nonoverlapping gene expression changes in the central nervous system of Drosophila. G3 Genes|Genomes|Genetics, 2, 789–802. https://doi.org/10.1534/g3.112.002998.
Higashiyama, H., Hirose, F., Yamaguchi, M., et al. (2002). Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell Death and Differentiation, 9, 264–273. https://doi.org/10.1038/sj.cdd.4400955.
Ihara, R., Matsukawa, K., Nagata, Y., et al. (2013). RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy. Human Molecular Genetics, 22, 4474–4484. https://doi.org/10.1093/hmg/ddt296.
Jantrapirom, S., Lo Piccolo, L., Yoshida, H., & Yamaguchi, M. (2018). Depletion of Ubiquilin induces an augmentation in soluble ubiquitinated Drosophila TDP-43 to drive neurotoxicity in the fly. Biochim Biophys Acta – Molecular Basis of Disease, 1864, 3038–3049. https://doi.org/10.1016/j.bbadis.2018.06.017.
Jolly, C., & Lakhotia, S. C. (2006). Human sat III and Drosophila hsrω transcripts: A common paradigm for regulation of nuclear RNA processing in stressed cells. Nucleic Acids Research, 34(19), 5508–5514.
Kim, S. H., Zhan, L., Hanson, K. A., & Tibbetts, R. S. (2012). High-content RNAi screening identifies the type 1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity. Human Molecular Genetics, 21, 4845–4856. https://doi.org/10.1093/hmg/dds321.
Kim, H. J., Kim, N. C., Wang, Y., et al. (2013a). Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS. Nature, 495, 467–473. https://doi.org/10.1038/nature11922.Prion-like.
Kim, N. C., Tresse, E., Kolaitis, R. M., et al. (2013b). VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron, 78, 65–80. https://doi.org/10.1016/j.neuron.2013.02.029.
Kim, S. H., Stiles, S. G., Feichtmeier, J. M., et al. (2018a). Mutation-dependent aggregation and toxicity in a Drosophila model for UBQLN2-associated ALS. Human Molecular Genetics, 27, 322–337. https://doi.org/10.1093/hmg/ddx403.
Kim, Y., Kim, H.-J., Cha, S. J., et al. (2018b). Genetic activation of parkin rescues TAF15-induced neurotoxicity in a Drosophila model of amyotrophic lateral sclerosis. Neurobiology of Aging, 73, 68–73. https://doi.org/10.1016/j.neurobiolaging.2018.09.023.
Kimura, Y., Fukushi, J., Hori, S., et al. (2013). Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system. Genes to Cells, 18, 1131–1143. https://doi.org/10.1111/gtc.12103.
Kumimoto, E. L., Fore, T. R., & Zhang, B. (2013). Transcriptome profiling following neuronal and glial expression of ALS-linked SOD1 in Drosophila. G3 Genes|Genomes|Genetics, 3, 695–708. https://doi.org/10.1534/g3.113.005850.
Kuranaga, E., Kanuka, H., Tonoki, A., et al. (2006). Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. Cell, 126, 583–596. https://doi.org/10.1016/j.cell.2006.05.048.
Kushimura, Y., Tokuda, T., Azuma, Y., et al. (2017). Loss of function mutant of ter94, Drosophila VCP, partially enhanced motor neuron degeneration induced by knockdown of TBPH, Drosophila TDP-43. Journal of the Neurological Sciences, 381, 563. https://doi.org/10.1016/j.jns.2017.08.1586.
Landers, J. E., Leclerc, A. L., Shi, L., et al. (2008). New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology, 70, 1179–1185.
Lanson, N. A., Maltare, A., King, H., et al. (2011). A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Human Molecular Genetics, 20, 2510–2523. https://doi.org/10.1093/hmg/ddr150.
Lee, K., Zhang, P., Kim, H., et al. (2016). C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell, 167, 774–788.
Lembke, K. M., Scudder, C., & Morton, D. B. (2017). Restoration of motor defects caused by loss of Drosophila TDP-43 by expression of the voltage-gated calcium channel, Cacophony, in central neurons. The Journal of Neuroscience, 37, 0554–0517. https://doi.org/10.1523/JNEUROSCI.0554-17.2017.
Li, A., Xie, Z., Dong, Y., et al. (2007). Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: In vivo interaction with early-onset Alzheimer disease genes. Human Molecular Genetics, 16, 2626–2639. https://doi.org/10.1093/hmg/ddm219.
Li, Y., Ray, P., Rao, E. J., et al. (2010). A Drosophila model for TDP-43 proteinopathy. Proceedings of the National Academy of Sciences, 107, 3169–3174. https://doi.org/10.1073/pnas.0913602107.
Li, Y. R., King, O. D., Shorter, J., & Gitler, A. D. (2013). Stress granules as crucibles of ALS pathogenesis. The Journal of Cell Biology, 201, 361–372. https://doi.org/10.1083/jcb.201302044.
Lo Piccolo, L., & Yamaguchi, M. (2017). RNAi of arcRNA hsrω affects sub-cellular localization of Drosophila FUS to drive neurodiseases. Experimental Neurology, 292, 125–134. https://doi.org/10.1016/j.expneurol.2017.03.011.
Lo Piccolo, L., Jantrapirom, S., Nagai, Y., & Yamaguchi, M. (2017). FUS toxicity is rescued by the modulation of lncRNA hsrω expression in Drosophila melanogaster. Scientific Reports, 7, 1–17. https://doi.org/10.1038/s41598-017-15944-y.
Lu, Y., Ferris, J., & Gao, F. B. (2009). Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Molecular Brain, 2, 1–10. https://doi.org/10.1186/1756-6606-2-30.
Machamer, J. B., Collins, S. E., & Lloyd, T. E. (2014). The ALS gene FUS regulates synaptic transmission at the Drosophila neuromuscular junction. Human Molecular Genetics, 23, 3810–3822. https://doi.org/10.1093/hmg/ddu094.
Mandrioli, J., D’Amico, R., Zucchi, E., et al. (2018). Rapamycin treatment for amyotrophic lateral sclerosis. Medicine (Baltimore), 97, e11119. https://doi.org/10.1097/MD.0000000000011119.
Martin, I., Jones, M. A., & Grotewiel, M. (2009). Manipulation of Sod1 expression ubiquitously, but not in the nervous system or muscle, impacts age-related parameters in Drosophila. FEBS Letters, 583, 2308–2314. https://doi.org/10.1016/j.febslet.2009.06.023.
Mathis, S., & Le Masson, G. (2018). RNA-targeted therapies and amyotrophic lateral sclerosis. Biomedicine, 6, 9. https://doi.org/10.3390/biomedicines6010009.
Matsukawa, K., Hashimoto, T., Matsumoto, T., et al. (2016). Familial Amyotrophic lateral sclerosis-linked mutations in profilin 1 exacerbate TDP-43-induced degeneration in the retina of Drosophila melanogaster through an increase in the cytoplasmic localization of TDP-43. The Journal of Biological Chemistry, 291, 23464–23476. https://doi.org/10.1074/jbc.M116.729152.
Matsumoto, T., Matsukawa, K., Watanabe, N., et al. (2018). Self-assembly of FUS through its low-complexity domain contributes to neurodegeneration. Human Molecular Genetics, 27, 1353–1365. https://doi.org/10.1093/hmg/ddy046.
Mccabe, B. D., Hom, S., Aberle, H., et al. (2004). Highwire regulates presynaptic BMP signaling essential for synaptic growth. Neuron, 41, 891–905. https://doi.org/10.1016/S0896-6273(04)00073-X.
Miguel, L., Frébourg, T., Campion, D., & Lecourtois, M. (2011). Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. Neurobiology of Disease, 41, 398–406. https://doi.org/10.1016/j.nbd.2010.10.007.
Miguel, L., Avequin, T., Delarue, M., et al. (2012). Accumulation of insoluble forms of FUS protein correlates with toxicity in Drosophila. Neurobiology of Aging, 33, 1008.e1–1008.e15. https://doi.org/10.1016/j.neurobiolaging.2011.10.008.
Millecamps, S., Salachas, F., Cazeneuve, C., et al. (2010). SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: Genotype–phenotype correlations. Journal of Medical Genetics, 47, 554–560.
Milton, V. J., Jarrett, H. E., Gowers, K., et al. (2011). Oxidative stress induces overgrowth of the Drosophila neuromuscular junction. Proceedings of the National Academy of Sciences, 108, 17521–17526. https://doi.org/10.1073/pnas.1014511108.
Mizielinska, S., Grönke, S., Niccoli, T., et al. (2014). C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science, 345(6201), 1192–1194.
Mizielinska, S., Ridler, C. E., Balendra, R., et al. (2017). Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathologica Communications, 5, 29. https://doi.org/10.1186/s40478-017-0432-x.
Mockett, R. J., Radyuk, S. N., Benes, J. J., et al. (2003). Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 100, 301–306. https://doi.org/10.1073/pnas.0136976100.
Moens, T. G., Mizielinska, S., Niccoli, T., et al. (2018). Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD. Acta Neuropathologica, 135, 445–457. https://doi.org/10.1007/s00401-017-1798-3.
Moustaqim-barrette, A., Lin, Y. Q., & Pradhan, S., et al. (2013). The Amyotrophic Lateral Sclerosis 8 protein, VAP, is required for ER protein quality control (pp. 1–47) Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Department of Molecular and Human Genetics Howard Hu.
Mushtaq, Z., Choudhury, S. D., Gangwar, S. K., et al. (2016). Human senataxin modulates structural plasticity of the neuromuscular junction in drosophila through a neuronally conserved TGFβ signalling pathway. Neurodegenerative Diseases, 16, 324–336. https://doi.org/10.1159/000445435.
Neumann, M., Sampathu, D. M., Kwong, L. K., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 314, 130–133.
Neumann, M., Roeber, S., Kretzschmar, H. A., et al. (2010). Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathologica, 118, 605–616. https://doi.org/10.1007/s00401-009-0581-5.Abundant.
Nishimura, A. L., Mitne-neto, M., Silva, H. C. A., et al. (2004). A mutation in the vesicle-trafficking protein VAPB Causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. American Journal of Human Genetics, 2, 822–831.
Orr, W. C., Mockett, R. J., Benes, J. J., & Sohal, R. S. (2003). Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster. The Journal of Biological Chemistry, 278, 26418–26422. https://doi.org/10.1074/jbc.M303095200.
Parkes, T. L., Elia, A. J., Dickinson, D., et al. (1998). Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nature Genetics, 19, 171–174. https://doi.org/10.1038/534.
Pennetta, G., Hiesinger, P. R., Fabian-Fine, R., et al. (2002). Drosophila VAP-33A directs bouton formation at neuromuscular junctions in a dosage-dependent manner. Neuron, 35, 291–306.
Pons, M., Miguel, L., Miel, C., et al. (2017). Splicing factors act as genetic modulators of TDP-43 production in a new autoregulatory TDP-43 Drosophila model. Human Molecular Genetics, 26, 3396–3408. https://doi.org/10.1093/hmg/ddx229.
Prudencio, M., Hart, P. J., Borchelt, D. R., & Andersen, P. M. (2009). Variation in aggregation propensities among ALS-associated variants of SOD1: Correlation to human disease. Human Molecular Genetics, 18, 3217–3226. https://doi.org/10.1093/hmg/ddp260.
Ratnaparkhi, A., Lawless, G. M., Schweizer, F. E., et al. (2008). A Drosophila model of ALS: Human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One, 3, e2334. https://doi.org/10.1371/journal.pone.0002334.
Renton, A. E., Chiò, A., & Traynor, B. J. (2014). State of play in amyotrophic lateral sclerosis genetics. Nature Neuroscience, 17, 17–23. https://doi.org/10.1038/nn.3584.
Romano, M., Buratti, E., Romano, G., et al. (2014). Evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins functionally interact with human and drosophila tar DNA-binding protein 43 (TDP-43). The Journal of Biological Chemistry, 289, 7121–7130. https://doi.org/10.1074/jbc.M114.548859.
Romano, G., Appocher, C., Scorzeto, M., et al. (2015). Glial TDP-43 regulates axon wrapping, GluRIIA clustering and fly motility by autonomous and non-autonomous mechanisms. Human Molecular Genetics, 24, 6134–6145. https://doi.org/10.1093/hmg/ddv330.
Romano, M., Feiguin, F., & Buratti, E. (2016). TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5′UTR. Brain Research, 1647, 50–56. https://doi.org/10.1016/j.brainres.2016.02.022.
Romano, G., Holodkov, N., Klima, R., et al. (2018). Downregulation of glutamic acid decarboxylase in Drosophila TDP- 43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses. Scientific Reports, 8, 1–12. https://doi.org/10.1038/s41598-018-19802-3.
Rosen, D. R., Siddique, T., Patterson, D., et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362, 59.
Rumpf, S., Bagley, J. A., Thompson-Peer, K. L., et al. (2014). Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism. Proceedings of the National Academy of Sciences, 111, 7331–7336. https://doi.org/10.1073/pnas.1406898111.
Şahin, A., Held, A., Bredvik, K., et al. (2017). Human SOD1 ALS mutations in a Drosophila knock-in model cause severe phenotypes and reveal dosage-sensitive gain- and loss-of-function components. Genetics, 205, 707–723. https://doi.org/10.1534/genetics.116.190850.
Sanhueza, M., Zechini, L., Gillespie, T., & Pennetta, G. (2014). Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles. Biology Open, 3, 59–71. https://doi.org/10.1242/bio.20137070.
Sanhueza, M., Chai, A., Smith, C., et al. (2015). Network analyses reveal novel aspects of ALS pathogenesis. PLoS Genetics, 11, 1–32. https://doi.org/10.1371/journal.pgen.1005107.
Sasayama, H., Shimamura, M., Tokuda, T., et al. (2012). Knockdown of the Drosophila fused in sarcoma (FUS) homologue causes deficient locomotive behavior and shortening of motoneuron terminal branches. PLoS One, 7. https://doi.org/10.1371/journal.pone.0039483.
Shahidullah, M., Le Marchand, S. J., Fei, H., et al. (2013). Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS. The Journal of Neuroscience, 33, 19590–19598. https://doi.org/10.1523/JNEUROSCI.3396-13.2013.
Sheng, Y., Chattopadhyay, M., Whitelegge, J., & Valentine, J. S. (2012). SOD1 aggregation and ALS: Role of metallation states and disulfide. Current topics in medicinal chemistry, 12(22), 2560–2572.
Simone, R., Balendra, R., Moens, T. G., et al. (2017). G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Molecular Medicine, 10, e201707850. https://doi.org/10.15252/emmm.201707850.
Steyaert, J., Scheveneels, W., Vanneste, J., et al. (2018). FUS-induced neurotoxicity in Drosophila is prevented by downregulating nucleocytoplasmic transport proteins. Human Molecular Genetics, 00, 1–14. https://doi.org/10.1093/hmg/ddy303.
Sun, J., & Tower, J. (1999). FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Molecular and Cellular Biology, 19, 216–228. https://doi.org/10.1128/MCB.19.1.216.
Sun, Z., Diaz, Z., Fang, X., et al. (2011). Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biology, 9, e1000614. https://doi.org/10.1371/journal.pbio.1000614.
Sun, Y., Dong, Y., Wang, J., et al. (2017). A novel mutation of VAPB in one Chinese familial amyotrophic lateral sclerosis pedigree and its clinical characteristics. Journal of Neurology, 264, 2387–2393. https://doi.org/10.1007/s00415-017-8628-3.
Takayama, Y., Itoh, R. E., Tsuyama, T., & Uemura, T. (2014). Age-dependent deterioration of locomotion in Drosophila melanogaster deficient in the homologue of amyotrophic lateral sclerosis 2. Genes to Cells, 19, 464–477. https://doi.org/10.1111/gtc.12146.
Tran, H., Almeida, S., Moore, J., et al. (2015). Differential toxicity of nuclear RNA foci versus dipeptide-repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron, 87, 1207–1214. https://doi.org/10.1016/j.neuron.2015.09.015.
Tsuda, H., Han, S. M., Yang, Y., et al. (2008). The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell, 133, 963–977. https://doi.org/10.1016/j.cell.2008.04.039.
Uechi, H., Kuranaga, E., Iriki, T., et al. (2018). Ubiquitin-binding protein CG5445 suppresses aggregation and cytotoxicity of amyotrophic lateral sclerosis-linked TDP-43 in Drosophila. Molecular and Cellular Biology, 38, e00195–e00117. https://doi.org/10.1128/MCB.00195-17.
van Blitterswijk, M., van Es, M. A., Hennekam, E. A., et al. (2012). Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Human Molecular Genetics, 21, 3776–3784. https://doi.org/10.1093/hmg/dds199.
Vance, C., Boris, R., Hortobágyi, T., et al. (2009). Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science, 323, 1208–1211.
Voigt, A., Herholz, D., Fiesel, F. C., et al. (2010). TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS One, 5. https://doi.org/10.1371/journal.pone.0012247.
Wang, J. W., Brent, J. R., Tomlinson, A., et al. (2011). The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span. The Journal of Clinical Investigation, 121, 4118–4126. https://doi.org/10.1172/JCI57883.
Wang, T., Xu, W., Qin, M., et al. (2016). Pathogenic mutations in the valosin-containing protein/p97(VCP) N-domain inhibit the SUMOylation of VCP and lead to impaired stress response. The Journal of Biological Chemistry, 291, 14373–14384. https://doi.org/10.1074/jbc.M116.729343.
Watson, M. R., Lagow, R. D., Xu, K., et al. (2008). A Drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. The Journal of Biological Chemistry, 283, 24972–24981. https://doi.org/10.1074/jbc.M804817200.
Wen, X., Tan, W., Westergard, T., et al. (2014). Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate invitro and invivo neuronal death. Neuron, 84, 1213–1225. https://doi.org/10.1016/j.neuron.2014.12.010.
West, R. J. H., Lu, Y., Marie, B., et al. (2015). Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia. The Journal of Cell Biology, 208, 931–947. https://doi.org/10.1083/jcb.201404066.
Wu, C. H., Giampetruzzi, A., Tran, H., et al. (2017). A Drosophila model of ALS reveals a partial loss of function of causative human PFN1 mutants. Human Molecular Genetics, 26, 2146–2155. https://doi.org/10.1093/hmg/ddx112.
Xia, R., Liu, Y., Yang, L., et al. (2012). Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS. Molecular Neurodegeneration, 7, 1–17. https://doi.org/10.1186/1750-1326-7-10.
Xia, Q., Wang, H., Hao, Z., et al. (2016). TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. The EMBO Journal, 35, 121–142. https://doi.org/10.15252/embj.201591998.
Xu, W., & Xu, J. (2018). C9orf72 dipeptide repeats cause selective neurodegeneration and cell-autonomous excitotoxicity in Drosophila glutamatergic neurons. The Journal of Neuroscience, 38(35), 7741–7752.
Xu, Z., Poidevin, M., Li, X., et al. (2013). Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proceedings of the National Academy of Sciences, 110, 7778–7783. https://doi.org/10.1073/pnas.1219643110.
Yadav, S., Thakur, R., Georgiev, P., et al. (2018). RDGBα localization and function at membrane contact sites is regulated by FFAT–VAP interactions. Journal of Cell Science, 131, jcs207985. https://doi.org/10.1242/jcs.207985.
Yamamoto, I., Azuma, Y., Kushimura, Y., et al. (2018). NPM-hMLF1 fusion protein suppresses defects of a Drosophila FTLD model expressing the human FUS gene. Scientific Reports, 8, 1–14. https://doi.org/10.1038/s41598-018-29716-9.
Yang, Z., Huh, S. U., Drennan, J. M., et al. (2012). Drosophila Vap-33 is required for axonal localization of Dscam isoforms. The Journal of Neuroscience, 32, 17241–17250. https://doi.org/10.1523/JNEUROSCI.2834-12.2012.
Yang, D., Abdallah, A., Li, Z., et al. (2015). FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathologica, 130, 525–535. https://doi.org/10.1007/s00401-015-1448-6.
Zhan, L., Xie, Q., & Tibbetts, R. S. (2014). Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration. Human Molecular Genetics, 1–16. https://doi.org/10.1093/hmg/ddu493.
Zhang, Y.-J., Jansen-West, K., Xu, Y.-F., et al. (2014). Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathologica, 128(4), 505–524. https://doi.org/10.1007/s00401-014-1336-5.
Zhang, K., Donnelly, C. J., Haeusler, A. R., et al. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature, 525, 56–61. https://doi.org/10.1038/nature14973.
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Chaplot, K., Ratnaparkhi, A., Ratnaparkhi, G. (2019). Understanding Motor Disorders Using Flies. In: Mutsuddi, M., Mukherjee, A. (eds) Insights into Human Neurodegeneration: Lessons Learnt from Drosophila. Springer, Singapore. https://doi.org/10.1007/978-981-13-2218-1_5
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