Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo

Abstract The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neur...

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Autores principales:	Jingti Deng, Carolina Koutras, Julien Donnelier, Mana Alshehri, Maryam Fotouhi, Martine Girard, Steve Casha, Peter S. McPherson, Stephen M. Robbins, Janice E. A. Braun
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3828e669537c4a758aa77d1df0d2eb5f
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spelling	oai:doaj.org-article:3828e669537c4a758aa77d1df0d2eb5f2021-12-02T11:52:26ZNeurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo10.1038/s41598-017-01115-62045-2322https://doaj.org/article/3828e669537c4a758aa77d1df0d2eb5f2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01115-6https://doaj.org/toc/2045-2322Abstract The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα. Extracellular vesicles (EV’s) have been implicated in a wide range of functions. However, the functional significance of neural EV’s remains to be established. Here we demonstrate that co-expression of CSPα with the disease-associated proteins, polyglutamine expanded protein 72Q huntingtinex°n1 or superoxide dismutase-1 (SOD-1G93A) leads to the cellular export of both 72Q huntingtinex°n1 and SOD-1G93A via EV’s. In contrast, the inactive CSPαHPD-AAA mutant does not facilitate elimination of misfolded proteins. Furthermore, CSPα-mediated export of 72Q huntingtinex°n1 is reduced by the polyphenol, resveratrol. Our results indicate that by assisting local lysosome/proteasome processes, CSPα-mediated removal of toxic proteins via EVs plays a central role in synaptic proteostasis and CSPα thus represents a potential therapeutic target for neurodegenerative diseases.Jingti DengCarolina KoutrasJulien DonnelierMana AlshehriMaryam FotouhiMartine GirardSteve CashaPeter S. McPhersonStephen M. RobbinsJanice E. A. BraunNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jingti Deng Carolina Koutras Julien Donnelier Mana Alshehri Maryam Fotouhi Martine Girard Steve Casha Peter S. McPherson Stephen M. Robbins Janice E. A. Braun Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
description	Abstract The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα. Extracellular vesicles (EV’s) have been implicated in a wide range of functions. However, the functional significance of neural EV’s remains to be established. Here we demonstrate that co-expression of CSPα with the disease-associated proteins, polyglutamine expanded protein 72Q huntingtinex°n1 or superoxide dismutase-1 (SOD-1G93A) leads to the cellular export of both 72Q huntingtinex°n1 and SOD-1G93A via EV’s. In contrast, the inactive CSPαHPD-AAA mutant does not facilitate elimination of misfolded proteins. Furthermore, CSPα-mediated export of 72Q huntingtinex°n1 is reduced by the polyphenol, resveratrol. Our results indicate that by assisting local lysosome/proteasome processes, CSPα-mediated removal of toxic proteins via EVs plays a central role in synaptic proteostasis and CSPα thus represents a potential therapeutic target for neurodegenerative diseases.
format	article
author	Jingti Deng Carolina Koutras Julien Donnelier Mana Alshehri Maryam Fotouhi Martine Girard Steve Casha Peter S. McPherson Stephen M. Robbins Janice E. A. Braun
author_facet	Jingti Deng Carolina Koutras Julien Donnelier Mana Alshehri Maryam Fotouhi Martine Girard Steve Casha Peter S. McPherson Stephen M. Robbins Janice E. A. Braun
author_sort	Jingti Deng
title	Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
title_short	Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
title_full	Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
title_fullStr	Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
title_full_unstemmed	Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
title_sort	neurons export extracellular vesicles enriched in cysteine string protein and misfolded protein cargo
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3828e669537c4a758aa77d1df0d2eb5f
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Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo

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