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Clusterin protects neurons against intracellular proteotoxicity

Clusterin protects neurons against intracellular proteotoxicity

Authors :
Jenna M. Gregory
Daniel R. Whiten
Rebecca A. Brown
Teresa P. Barros
Janet R. Kumita
Justin J. Yerbury
Sandeep Satapathy
Karina McDade
Colin Smith
Leila M. Luheshi
Christopher M. Dobson
Mark R. Wilson
Source :
Acta Neuropathologica Communications, Vol 5, Iss 1, Pp 1-16 (2017)
Publication Year :
2017
Publisher :
BMC, 2017.

Abstract

Abstract It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis-associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems. We have shown that clusterin directly interacts with TDP-43 in vitro and potently inhibits its aggregation, and observed that in ER stressed neuronal cells, clusterin co-localized with TDP-43 and specifically reduced the numbers of cytoplasmic inclusions. We further showed that the expression of TDP-43 in transgenic Drosophila neurons induced ER stress and that co-expression of clusterin resulted in a dramatic clearance of mislocalized TDP-43 from motor neuron axons, partially rescued locomotor activity and significantly extended lifespan. We also showed that in Drosophila photoreceptor cells, clusterin co-expression gave ER stress-dependent protection against proteotoxicity arising from both Huntingtin-Q128 and mutant (R406W) human tau. We therefore conclude that increased expression of clusterin can provide an important defense against intracellular proteotoxicity under conditions that mimic specific features of neurodegenerative disease.

Details

Language :
English
ISSN :
20515960
Volume :
5
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Acta Neuropathologica Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.21bc7900713e4ebdb657794a389341be
Document Type :
article
Full Text :
https://doi.org/10.1186/s40478-017-0481-1