Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.

Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are a...

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Autores principales:	Hemi Dimant, Liya Zhu, Laura N Kibuuka, Zhanyun Fan, Bradley T Hyman, Pamela J McLean
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dee3e3b4dd7e4f65acf6ea5d3b17cf92
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spelling	oai:doaj.org-article:dee3e3b4dd7e4f65acf6ea5d3b17cf922021-11-18T08:26:28ZDirect visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.1932-620310.1371/journal.pone.0092098https://doaj.org/article/dee3e3b4dd7e4f65acf6ea5d3b17cf922014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24664141/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity. Here we use a gene therapy approach to evaluate the applicability of the Hsp70 co-chaperone CHIP (C-terminal Hsp70 interacting protein) as a therapeutic candidate and examine its direct effect on alpha synuclein aggregates in vivo. Utilizing a novel viral vector mediated rat model to directly detect alpha synuclein aggregates, we show that CHIP can mediate the degradation of alpha synuclein aggregates in vivo. However, our studies also reveal that CHIP may potentially degrade tyrosine hydroxylase which would compromise the applicability of CHIP as a therapeutic approach for Parkinson's disease.Hemi DimantLiya ZhuLaura N KibuukaZhanyun FanBradley T HymanPamela J McLeanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e92098 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hemi Dimant Liya Zhu Laura N Kibuuka Zhanyun Fan Bradley T Hyman Pamela J McLean Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
description	Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity. Here we use a gene therapy approach to evaluate the applicability of the Hsp70 co-chaperone CHIP (C-terminal Hsp70 interacting protein) as a therapeutic candidate and examine its direct effect on alpha synuclein aggregates in vivo. Utilizing a novel viral vector mediated rat model to directly detect alpha synuclein aggregates, we show that CHIP can mediate the degradation of alpha synuclein aggregates in vivo. However, our studies also reveal that CHIP may potentially degrade tyrosine hydroxylase which would compromise the applicability of CHIP as a therapeutic approach for Parkinson's disease.
format	article
author	Hemi Dimant Liya Zhu Laura N Kibuuka Zhanyun Fan Bradley T Hyman Pamela J McLean
author_facet	Hemi Dimant Liya Zhu Laura N Kibuuka Zhanyun Fan Bradley T Hyman Pamela J McLean
author_sort	Hemi Dimant
title	Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
title_short	Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
title_full	Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
title_fullStr	Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
title_full_unstemmed	Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.
title_sort	direct visualization of chip-mediated degradation of alpha-synuclein in vivo: implications for pd therapeutics.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/dee3e3b4dd7e4f65acf6ea5d3b17cf92
work_keys_str_mv	AT hemidimant directvisualizationofchipmediateddegradationofalphasynucleininvivoimplicationsforpdtherapeutics AT liyazhu directvisualizationofchipmediateddegradationofalphasynucleininvivoimplicationsforpdtherapeutics AT laurankibuuka directvisualizationofchipmediateddegradationofalphasynucleininvivoimplicationsforpdtherapeutics AT zhanyunfan directvisualizationofchipmediateddegradationofalphasynucleininvivoimplicationsforpdtherapeutics AT bradleythyman directvisualizationofchipmediateddegradationofalphasynucleininvivoimplicationsforpdtherapeutics AT pamelajmclean directvisualizationofchipmediateddegradationofalphasynucleininvivoimplicationsforpdtherapeutics
_version_	1718421832016592896

Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.

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