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Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila.
- Source :
-
FEBS letters [FEBS Lett] 2020 Sep; Vol. 594 (17), pp. 2800-2818. Date of Electronic Publication: 2020 Jun 28. - Publication Year :
- 2020
-
Abstract
- Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type 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-type MATR3, demonstrating that the disease-linked 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.<br /> (© 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Subjects :
- Amyotrophic Lateral Sclerosis metabolism
Amyotrophic Lateral Sclerosis pathology
Animals
Animals, Genetically Modified
Brain metabolism
Brain pathology
Disease Models, Animal
Drosophila Proteins antagonists & inhibitors
Drosophila Proteins metabolism
Drosophila melanogaster metabolism
Epistasis, Genetic
Flight, Animal physiology
Gene Expression
Humans
Longevity genetics
Motor Neurons pathology
Muscles metabolism
Muscles pathology
Muscular Diseases metabolism
Muscular Diseases pathology
Nuclear Matrix-Associated Proteins metabolism
Phenotype
RNA, Messenger genetics
RNA, Messenger metabolism
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
RNA-Binding Proteins metabolism
Transgenes
Wings, Animal metabolism
Wings, Animal pathology
Amyotrophic Lateral Sclerosis genetics
Axonal Transport genetics
Drosophila Proteins genetics
Drosophila melanogaster genetics
Motor Neurons metabolism
Muscular Diseases genetics
Nuclear Matrix-Associated Proteins genetics
RNA-Binding Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3468
- Volume :
- 594
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- FEBS letters
- Publication Type :
- Academic Journal
- Accession number :
- 32515490
- Full Text :
- https://doi.org/10.1002/1873-3468.13858