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Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease‐linked MATR3 mutations in Drosophila
Author(s) -
Zhao Melody,
Kao Ching Serena,
Arndt Claudia,
Tran David Duc,
Cho Woo In,
Maksimovic Katarina,
Chen Xiao Xiao Lily,
Khan Mashiat,
Zhu Hongxian,
Qiao Julia,
Peng Kailong,
Hong Jingyao,
Xu Jialu,
Kim Deanna,
Kim Jihye Rachel,
Lee Jooyun,
Bruggen Rebekah,
Yoon Wan Hee,
Park Jeehye
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13858
Subject(s) - amyotrophic lateral sclerosis , biology , gene knockdown , mutant , genetics , genetic screen , phenotype , microbiology and biotechnology , mutation , gene , disease , medicine , pathology
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.