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ALS-associated mutant FUS inhibits macroautophagy which is restored by overexpression of Rab1
Citation
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]
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Copyright Statement
Copyright 2015 Cell Death Differentiation Association Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
DOI: doi:10.1038/cddiscovery.2015.30
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.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | ALS, Motor Neuron Disease, Frontotemporal DEmentia , FUS, Autophagy |
| Research Division: | Medical and Health Sciences |
| Research Group: | Neurosciences |
| Research Field: | Cellular Nervous System |
| Objective Division: | Health |
| Objective Group: | Clinical Health (Organs, Diseases and Abnormal Conditions) |
| Objective Field: | Nervous System and Disorders |
| Author: | King, AE (Associate Professor Anna King) |
| Author: | Atkinson, RAK (Mrs Rachel Atkinson) |
| ID Code: | 105373 |
| Year Published: | 2015 |
| Deposited By: | Wicking Dementia Research and Education Centre |
| Deposited On: | 2015-12-22 |
| Last Modified: | 2018-02-17 |
| Downloads: | 61 View Download Statistics |
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