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Global Rhes knockout in the Q175 Huntington’s disease mouse model

Huntington’s disease (HD) results from an expansion mutation in the polyglutamine tract in huntingtin. Although huntingtin is ubiquitously expressed in the body, the striatum suffers the most severe pathology. Rhes is a Ras-related small GTP-binding protein highly expressed in the striatum that has...

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Autores principales: Heikkinen, Taneli, Bragge, Timo, Kuosmanen, Juha, Parkkari, Teija, Gustafsson, Sanna, Kwan, Mei, Beltran, Jose, Ghavami, Afshin, Subramaniam, Srinivasa, Shahani, Neelam, Ramírez-Jarquín, Uri Nimrod, Park, Larry, Muñoz-Sanjuán, Ignacio, Marchionini, Deanna M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516231/
https://www.ncbi.nlm.nih.gov/pubmed/34648564
http://dx.doi.org/10.1371/journal.pone.0258486
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author Heikkinen, Taneli
Bragge, Timo
Kuosmanen, Juha
Parkkari, Teija
Gustafsson, Sanna
Kwan, Mei
Beltran, Jose
Ghavami, Afshin
Subramaniam, Srinivasa
Shahani, Neelam
Ramírez-Jarquín, Uri Nimrod
Park, Larry
Muñoz-Sanjuán, Ignacio
Marchionini, Deanna M.
author_facet Heikkinen, Taneli
Bragge, Timo
Kuosmanen, Juha
Parkkari, Teija
Gustafsson, Sanna
Kwan, Mei
Beltran, Jose
Ghavami, Afshin
Subramaniam, Srinivasa
Shahani, Neelam
Ramírez-Jarquín, Uri Nimrod
Park, Larry
Muñoz-Sanjuán, Ignacio
Marchionini, Deanna M.
author_sort Heikkinen, Taneli
collection PubMed
description Huntington’s disease (HD) results from an expansion mutation in the polyglutamine tract in huntingtin. Although huntingtin is ubiquitously expressed in the body, the striatum suffers the most severe pathology. Rhes is a Ras-related small GTP-binding protein highly expressed in the striatum that has been reported to modulate mTOR and sumoylation of mutant huntingtin to alter HD mouse model pathogenesis. Reports have varied on whether Rhes reduction is desirable for HD. Here we characterize multiple behavioral and molecular endpoints in the Q175 HD mouse model with genetic Rhes knockout (KO). Genetic RhesKO in the Q175 female mouse resulted in both subtle attenuation of Q175 phenotypic features, and detrimental effects on other kinematic features. The Q175 females exhibited measurable pathogenic deficits, as measured by MRI, MRS and DARPP32, however, RhesKO had no effect on these readouts. Additionally, RhesKO in Q175 mixed gender mice deficits did not affect mTOR signaling, autophagy or mutant huntingtin levels. We conclude that global RhesKO does not substantially ameliorate or exacerbate HD mouse phenotypes in Q175 mice.
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spelling pubmed-85162312021-10-15 Global Rhes knockout in the Q175 Huntington’s disease mouse model Heikkinen, Taneli Bragge, Timo Kuosmanen, Juha Parkkari, Teija Gustafsson, Sanna Kwan, Mei Beltran, Jose Ghavami, Afshin Subramaniam, Srinivasa Shahani, Neelam Ramírez-Jarquín, Uri Nimrod Park, Larry Muñoz-Sanjuán, Ignacio Marchionini, Deanna M. PLoS One Research Article Huntington’s disease (HD) results from an expansion mutation in the polyglutamine tract in huntingtin. Although huntingtin is ubiquitously expressed in the body, the striatum suffers the most severe pathology. Rhes is a Ras-related small GTP-binding protein highly expressed in the striatum that has been reported to modulate mTOR and sumoylation of mutant huntingtin to alter HD mouse model pathogenesis. Reports have varied on whether Rhes reduction is desirable for HD. Here we characterize multiple behavioral and molecular endpoints in the Q175 HD mouse model with genetic Rhes knockout (KO). Genetic RhesKO in the Q175 female mouse resulted in both subtle attenuation of Q175 phenotypic features, and detrimental effects on other kinematic features. The Q175 females exhibited measurable pathogenic deficits, as measured by MRI, MRS and DARPP32, however, RhesKO had no effect on these readouts. Additionally, RhesKO in Q175 mixed gender mice deficits did not affect mTOR signaling, autophagy or mutant huntingtin levels. We conclude that global RhesKO does not substantially ameliorate or exacerbate HD mouse phenotypes in Q175 mice. Public Library of Science 2021-10-14 /pmc/articles/PMC8516231/ /pubmed/34648564 http://dx.doi.org/10.1371/journal.pone.0258486 Text en © 2021 Heikkinen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Heikkinen, Taneli
Bragge, Timo
Kuosmanen, Juha
Parkkari, Teija
Gustafsson, Sanna
Kwan, Mei
Beltran, Jose
Ghavami, Afshin
Subramaniam, Srinivasa
Shahani, Neelam
Ramírez-Jarquín, Uri Nimrod
Park, Larry
Muñoz-Sanjuán, Ignacio
Marchionini, Deanna M.
Global Rhes knockout in the Q175 Huntington’s disease mouse model
title Global Rhes knockout in the Q175 Huntington’s disease mouse model
title_full Global Rhes knockout in the Q175 Huntington’s disease mouse model
title_fullStr Global Rhes knockout in the Q175 Huntington’s disease mouse model
title_full_unstemmed Global Rhes knockout in the Q175 Huntington’s disease mouse model
title_short Global Rhes knockout in the Q175 Huntington’s disease mouse model
title_sort global rhes knockout in the q175 huntington’s disease mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516231/
https://www.ncbi.nlm.nih.gov/pubmed/34648564
http://dx.doi.org/10.1371/journal.pone.0258486
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