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ALS-associated mutant FUS inhibits macroautophagy which is restored by overexpression of Rab1


Soo, KY and Sultana, J and King, AE and Atkinson, RAK and Warraich, ST and Sundaramoorthy, V and Blair, I and Farg, MA and Atkin, JD, ALS-associated mutant FUS inhibits macroautophagy which is restored by overexpression of Rab1, Cell Death Discovery, 1 Article 15030. ISSN 2058-7716 (2015) [Refereed Article]


Copyright Statement

Copyright 2015 Cell Death Differentiation Association Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

DOI: doi:10.1038/cddiscovery.2015.30


Amyotrophic lateral sclerosis (ALS) is characterised by the formation of intracellular misfolded protein inclusions that form in motor neurons. Autophagy is the major degradation pathway for aggregate-prone proteins within lysosomes. Autophagy begins by the production of the omegasome, forming the autophagosome membrane, which then fuses with the lysosome. Mutations in fused in sarcoma (FUS) cause 5% of familial ALS cases and FUS-positive inclusions are also formed in sporadic ALS tissues. In this study, we demonstrate that the expression of ALS-associated mutant FUS impairs autophagy in neuronal cells. In mutant FUS-expressing neuronal cells, accumulation of ubiquitinated proteins and autophagy substrates p62 and NBR1 was detected, and formation of both the omegasome and autophagosome was inhibited in these cells. However, overexpression of Rab1 rescued these defects, suggesting that Rab1 is protective in ALS. The number of LC3-positive vesicles was also increased in motor neurons from the spinal cord of an ALS patient carrying a FUS (R521C) mutation compared with a control patient, providing additional evidence that autophagy is dysregulated in mutant FUS-associated ALS. This study provides further understanding of the intricate autophagy system and neurodegeneration in ALS.

Item Details

Item Type:Refereed Article
Keywords:ALS, Motor Neuron Disease, Frontotemporal DEmentia , FUS, Autophagy
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Cellular nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:King, AE (Professor Anna King)
UTAS Author:Atkinson, RAK (Dr Rachel Atkinson)
ID Code:105373
Year Published:2015
Web of Science® Times Cited:44
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2015-12-22
Last Modified:2018-02-17
Downloads:200 View Download Statistics

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