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To investigate the mechanisms underlying <jats:italic>MATR3<\/jats:italic> mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild\u2010type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild\u2010type MATR3, demonstrating that the disease\u2010linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.<\/jats:p>","DOI":"10.1002\/1873-3468.13858","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T11:10:59Z","timestamp":1591701059000},"page":"2800-2818","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease\u2010linked MATR3 mutations in <i>Drosophila<\/i>"],"prefix":"10.1002","volume":"594","author":[{"given":"Melody","family":"Zhao","sequence":"first","affiliation":[{"name":"Genetics and Genome Biology Program The Hospital for Sick Children Toronto Canada"},{"name":"Department of Molecular Genetics University of Toronto Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching 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