Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autor principal: Subramaniam, Srinivasa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2022
Materias:
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
_version_ 1784791816973844480
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
work_keys_str_mv AT subramaniamsrinivasa striatalinductionandspreadofthehuntingtonsdiseaseproteinanovelrhesroute