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Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice

Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alp...

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Autores principales: Liu, Xiaoguang, Balaraman, Kaluvu, Lynch, Ciarán C., Hebron, Michaeline, Shah, Priya Ketankumar, Hu, Shicheng, Stevenson, Max, Wolf, Christian, Moussa, Charbel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330474/
https://www.ncbi.nlm.nih.gov/pubmed/35897705
http://dx.doi.org/10.3390/ijms23158131
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author Liu, Xiaoguang
Balaraman, Kaluvu
Lynch, Ciarán C.
Hebron, Michaeline
Shah, Priya Ketankumar
Hu, Shicheng
Stevenson, Max
Wolf, Christian
Moussa, Charbel
author_facet Liu, Xiaoguang
Balaraman, Kaluvu
Lynch, Ciarán C.
Hebron, Michaeline
Shah, Priya Ketankumar
Hu, Shicheng
Stevenson, Max
Wolf, Christian
Moussa, Charbel
author_sort Liu, Xiaoguang
collection PubMed
description Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13(+/+) mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13(+/−)) or completely (USP13(−/−)) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13(+/+)), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies.
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spelling pubmed-93304742022-07-29 Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice Liu, Xiaoguang Balaraman, Kaluvu Lynch, Ciarán C. Hebron, Michaeline Shah, Priya Ketankumar Hu, Shicheng Stevenson, Max Wolf, Christian Moussa, Charbel Int J Mol Sci Article Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13(+/+) mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13(+/−)) or completely (USP13(−/−)) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13(+/+)), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies. MDPI 2022-07-23 /pmc/articles/PMC9330474/ /pubmed/35897705 http://dx.doi.org/10.3390/ijms23158131 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Xiaoguang
Balaraman, Kaluvu
Lynch, Ciarán C.
Hebron, Michaeline
Shah, Priya Ketankumar
Hu, Shicheng
Stevenson, Max
Wolf, Christian
Moussa, Charbel
Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
title Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
title_full Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
title_fullStr Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
title_full_unstemmed Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
title_short Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
title_sort inhibition of ubiquitin-specific protease-13 improves behavioral performance in alpha-synuclein expressing mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330474/
https://www.ncbi.nlm.nih.gov/pubmed/35897705
http://dx.doi.org/10.3390/ijms23158131
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