Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the <i>SACS</i> gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in pro...

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Autores principales:	Suran Nethisinghe, Rosella Abeti, Maheswaran Kesavan, W. Christian Wigley, Paola Giunti
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ARSACS ataxia vimentin KU-32 Hsp90 inhibition Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/06be726115614437a0d4ce65adfa79f7
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id	oai:doaj.org-article:06be726115614437a0d4ce65adfa79f7
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spelling	oai:doaj.org-article:06be726115614437a0d4ce65adfa79f72021-11-11T17:10:45ZHsp90 Inhibition: A Promising Therapeutic Approach for ARSACS10.3390/ijms2221117221422-00671661-6596https://doaj.org/article/06be726115614437a0d4ce65adfa79f72021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11722https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the <i>SACS</i> gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.Suran NethisingheRosella AbetiMaheswaran KesavanW. Christian WigleyPaola GiuntiMDPI AGarticleARSACSataxiavimentinKU-32Hsp90 inhibitionBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11722, p 11722 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ARSACS ataxia vimentin KU-32 Hsp90 inhibition Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	ARSACS ataxia vimentin KU-32 Hsp90 inhibition Biology (General) QH301-705.5 Chemistry QD1-999 Suran Nethisinghe Rosella Abeti Maheswaran Kesavan W. Christian Wigley Paola Giunti Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS
description	Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the <i>SACS</i> gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.
format	article
author	Suran Nethisinghe Rosella Abeti Maheswaran Kesavan W. Christian Wigley Paola Giunti
author_facet	Suran Nethisinghe Rosella Abeti Maheswaran Kesavan W. Christian Wigley Paola Giunti
author_sort	Suran Nethisinghe
title	Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS
title_short	Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS
title_full	Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS
title_fullStr	Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS
title_full_unstemmed	Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS
title_sort	hsp90 inhibition: a promising therapeutic approach for arsacs
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/06be726115614437a0d4ce65adfa79f7
work_keys_str_mv	AT surannethisinghe hsp90inhibitionapromisingtherapeuticapproachforarsacs AT rosellaabeti hsp90inhibitionapromisingtherapeuticapproachforarsacs AT maheswarankesavan hsp90inhibitionapromisingtherapeuticapproachforarsacs AT wchristianwigley hsp90inhibitionapromisingtherapeuticapproachforarsacs AT paolagiunti hsp90inhibitionapromisingtherapeuticapproachforarsacs
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Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS

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