Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila

FEBS Letters

article

Melody Zhao¹  Ching Serena Kao¹  Claudia Arndt¹  David Duc Tran¹  Woo In Cho¹  Katarina Maksimovic¹  Xiao Xiao Lily Chen¹  Mashiat Khan¹  Hongxian Zhu¹  Julia Qiao¹  Kailong Peng¹  Jingyao Hong¹  Jialu Xu¹  Deanna Kim¹  Jihye Rachel Kim¹  Jooyun Lee¹  Rebekah van Bruggen¹  Wan Hee Yoon³  Jeehye Park¹ 

[1] Genetics and Genome Biology Program, The Hospital for Sick Children;Department of Molecular Genetics, University of Toronto;Aging & Metabolism Research Program, Oklahoma Medical Research Foundation

关键词: amyotrophic lateral sclerosis;    Drosophila;    genetic screen;    MATR3;    multisystem proteinopathy;   

DOI  :  10.1002/1873-3468.13858

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown