Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease‐linked MATR3 mutations in Drosophila
Open Access
- 9 June 2020
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 594 (17), 2800-2818
- https://doi.org/10.1002/1873-3468.13858
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.Funding Information
- Canada Research Chairs
- ALS Society of Canada
- Fondation Brain Canada
This publication has 75 references indexed in Scilit:
- dnc-1/dynactin 1 Knockdown Disrupts Transport of Autophagosomes and Induces Motor Neuron DegenerationPLOS ONE, 2013
- Matrin 3 Binds and Stabilizes mRNAPLOS ONE, 2011
- Matrin 3 as a key regulator of endothelial cell survivalExperimental Cell Research, 2011
- Drosophila Porin/VDAC Affects Mitochondrial MorphologyPLOS ONE, 2010
- CF2 Represses Actin 88F Gene Expression and Maintains Filament Balance during Indirect Flight Muscle Development in DrosophilaPLOS ONE, 2010
- Manipulation of Sod1 expression ubiquitously, but not in the nervous system or muscle, impacts age‐related parameters in DrosophilaFEBS Letters, 2009
- Autosomal-Dominant Distal Myopathy Associated with a Recurrent Missense Mutation in the Gene Encoding the Nuclear Matrix Protein, Matrin 3American Journal of Human Genetics, 2009
- Guide to Understanding Drosophila Models of Neurodegenerative DiseasesPLoS Biology, 2008
- An optimized transgenesis system for Drosophila using germ-line-specific φC31 integrasesProceedings of the National Academy of Sciences of the United States of America, 2007
- A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1The EMBO Journal, 2006