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

doi:10.1016/j.isci.2020.101700

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

Macquarie University Centre for Motor Neuron Disease Research

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	101700
Pages (from-to)	1-13
Number of pages	28
Journal	iScience
Volume	23
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2020.101700
Publication status	Published - 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

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Publisher version (open access)Final published version, 4.94 MBLicence: CC BY-NC-ND

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title = "Ubiquitin homeostasis is disrupted in TDP-43 and FUS cell models of ALS",

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.",

keywords = "Molecular Biology, Neuroscience, Protein Folding",

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

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.",

year = "2020",

month = nov,

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doi = "10.1016/j.isci.2020.101700",

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AU - Farrawell, Natalie E.

AU - McAlary, Luke

AU - Lum, Jeremy S.

AU - Chisholm, Christen G.

AU - Warraich, Sadaf T.

AU - Blair, Ian P.

AU - Vine, Kara L.

AU - Saunders, Darren N.

AU - Yerbury, Justin J.

N1 - 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.

PY - 2020/11/20

Y1 - 2020/11/20

N2 - 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.

AB - 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.

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KW - Protein Folding

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

Abstract

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Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis

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

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Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis

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