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Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route
The CAG/CAA expansion encoding polyQ huntingtin (mutant huntingtin [mHTT]) causes Huntington’s disease (HD), which is characterized by atrophy and loss of striatal medium spiny neurons (MSNs), which are preceded by neuropathological alterations in the cortex. Previous studies have shown that mHTT ca...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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IOS Press
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484121/ https://www.ncbi.nlm.nih.gov/pubmed/35871361 http://dx.doi.org/10.3233/JHD-220548 |
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author | Subramaniam, Srinivasa |
author_facet | Subramaniam, Srinivasa |
author_sort | Subramaniam, Srinivasa |
collection | PubMed |
description | The CAG/CAA expansion encoding polyQ huntingtin (mutant huntingtin [mHTT]) causes Huntington’s disease (HD), which is characterized by atrophy and loss of striatal medium spiny neurons (MSNs), which are preceded by neuropathological alterations in the cortex. Previous studies have shown that mHTT can spread in the brain, but the mechanisms involved in the stereotyped degeneration and dysfunction of the neurons from the striatum to the cortex remain unclear. In this study, we found that the mHTT expression initially restricted in the striatum later spread to the cortical regions in mouse brains. Such transmission was diminished in mice that lacked the striatal-enriched protein Ras-homolog enriched in the striatum (Rhes). Rhes restricted to MSNs was also found in the cortical layers of the brain, indicating a new transmission route for the Rhes protein to the brain. Mechanistically, Rhes promotes such transmission via a direct cell-to-cell contact mediated by tunneling nanotubes (TNTs), the membranous protrusions that enable the transfer of mHTT, Rhes, and other vesicular cargoes. These transmission patterns suggest that Rhes and mHTT are likely co-transported in the brain using TNT-like cell-to-cell contacts. On the basis of these new results, a perspective is presented in this review: Rhes may ignite the mHTT transmission from the striatum that may coincide with HD onset and disease progression through an anatomically connected striato-cortical retrograde route. |
format | Online Article Text |
id | pubmed-9484121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | IOS Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-94841212022-09-30 Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route Subramaniam, Srinivasa J Huntingtons Dis Review The CAG/CAA expansion encoding polyQ huntingtin (mutant huntingtin [mHTT]) causes Huntington’s disease (HD), which is characterized by atrophy and loss of striatal medium spiny neurons (MSNs), which are preceded by neuropathological alterations in the cortex. Previous studies have shown that mHTT can spread in the brain, but the mechanisms involved in the stereotyped degeneration and dysfunction of the neurons from the striatum to the cortex remain unclear. In this study, we found that the mHTT expression initially restricted in the striatum later spread to the cortical regions in mouse brains. Such transmission was diminished in mice that lacked the striatal-enriched protein Ras-homolog enriched in the striatum (Rhes). Rhes restricted to MSNs was also found in the cortical layers of the brain, indicating a new transmission route for the Rhes protein to the brain. Mechanistically, Rhes promotes such transmission via a direct cell-to-cell contact mediated by tunneling nanotubes (TNTs), the membranous protrusions that enable the transfer of mHTT, Rhes, and other vesicular cargoes. These transmission patterns suggest that Rhes and mHTT are likely co-transported in the brain using TNT-like cell-to-cell contacts. On the basis of these new results, a perspective is presented in this review: Rhes may ignite the mHTT transmission from the striatum that may coincide with HD onset and disease progression through an anatomically connected striato-cortical retrograde route. IOS Press 2022-08-30 /pmc/articles/PMC9484121/ /pubmed/35871361 http://dx.doi.org/10.3233/JHD-220548 Text en © 2022 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Subramaniam, Srinivasa Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route |
title | Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route |
title_full | Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route |
title_fullStr | Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route |
title_full_unstemmed | Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route |
title_short | Striatal Induction and Spread of the Huntington’s Disease Protein: A Novel Rhes Route |
title_sort | striatal induction and spread of the huntington’s disease protein: a novel rhes route |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484121/ https://www.ncbi.nlm.nih.gov/pubmed/35871361 http://dx.doi.org/10.3233/JHD-220548 |
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