The FUS gene is dual-coding with both proteins contributing to FUS-mediated toxicity

被引：31

作者：

Brunet M.A. ^{[1
,2
]}

Jacques J.-F. ^{[1
,2
]}

Nassari S. ^{[3
]}

Tyzack G.E. ^{[4
,5
]}

McGoldrick P. ^{[6
]}

Zinman L. ^{[7
]}

Jean S. ^{[3
]}

Robertson J. ^{[6
]}

Patani R. ^{[4
,5
]}

Roucou X. ^{[1
,2
]}

机构：

[1] Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC

[2] PROTEO, Quebec Network for Research on Protein Function, Structure, and Engineering, Quebec, QC

[3] Immunology and Cell Biology Department, Université de Sherbrooke, Sherbrooke, QC

[4] The Francis Crick Institute, London

[5] Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London

[6] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON

[7] Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON

来源：

The EMBO Reports | 2021年 / 22卷 / 1期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

alternative ORF; amyotrophic lateral sclerosis; dual coding; FUS; polycistronic;

D O I：

10.15252/embr.202050640

中图分类号：

学科分类号：

摘要：

Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over-expression of wild-type FUS and/or amyotrophic lateral sclerosis-linked FUS mutants is known to trigger toxic mechanisms in different models. These include inhibition of autophagy, loss of mitochondrial potential and accumulation of cytoplasmic aggregates. We find that altFUS, not FUS, is responsible for the inhibition of autophagy, and pivotal in mitochondrial potential loss and accumulation of cytoplasmic aggregates. Suppression of altFUS expression in a Drosophila model of FUS-related toxicity protects against neurodegeneration. Some mutations found in ALS patients are overlooked because of their synonymous effect on the FUS protein. Yet, we show they exert a deleterious effect causing missense mutations in the overlapping altFUS protein. These findings demonstrate that FUS is a bicistronic gene and suggests that both proteins, FUS and altFUS, cooperate in toxic mechanisms. © 2020 The Authors. Published under the terms of the CC BY 4.0 license

引用

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