Ubiquitin homeostasis is disrupted in TDP-43 and FUS cell models of ALS

Natalie E. Farrawell, Luke McAlary, Jeremy S. Lum, Christen G. Chisholm, Sadaf T. Warraich, Ian P. Blair, Kara L. Vine, Darren N. Saunders, Justin J. Yerbury*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Downloads (Pure)

Abstract

A major feature of amyotrophic lateral sclerosis (ALS) pathology is the accumulation of ubiquitin (Ub) into intracellular inclusions. This sequestration of Ub may reduce the availability of free Ub, disrupting Ub homeostasis and ultimately compromising cellular function and survival. We previously reported significant disturbance of Ub homeostasis in neuronal-like cells expressing mutant SOD1. Here, we show that Ub homeostasis is also perturbed in neuronal-like cells expressing either TDP-43 or FUS. The expression of mutant TDP-43 and mutant FUS led to UPS dysfunction, which was associated with a redistribution of Ub and depletion of the free Ub pool. Redistribution of Ub is also a feature of sporadic ALS, with an increase in Ub signal associated with inclusions and no compensatory increase in Ub expression. Together, these findings suggest that alterations to Ub homeostasis caused by the misfolding and aggregation of ALS-associated proteins play an important role in the pathogenesis of ALS.

Original languageEnglish
Article number101700
Pages (from-to)1-13
Number of pages28
JournaliScience
Volume23
Issue number11
DOIs
Publication statusPublished - 20 Nov 2020

Bibliographical note

Copyright the Author(s) 2020. 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.

Keywords

  • Molecular Biology
  • Neuroscience
  • Protein Folding

Fingerprint Dive into the research topics of 'Ubiquitin homeostasis is disrupted in TDP-43 and FUS cell models of ALS'. Together they form a unique fingerprint.

Cite this