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

K. Y. Soo, J. Sultana, A. E. King, R. A. K. Atkinson, S. T. Warraich, V. Sundaramoorthy, I. Blair, M. A. Farg, J. D. Atkin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)
4 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number15030
Pages (from-to)1-12
Number of pages12
JournalCell Death Discovery
Volume1
Issue number1
DOIs
Publication statusPublished - 21 Dec 2015

Bibliographical note

Copyright Cell Death Differentiation Association 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Fingerprint

Dive into the research topics of 'ALS-associated mutant FUS inhibits macroautophagy which is restored by overexpression of Rab1'. Together they form a unique fingerprint.

Cite this