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A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endo...

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Detalles Bibliográficos
Autores principales: Romo, Lindsay, Mohn, Emily S., Aronin, Neil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004895/
https://www.ncbi.nlm.nih.gov/pubmed/29865084
http://dx.doi.org/10.3233/JHD-180292
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author Romo, Lindsay
Mohn, Emily S.
Aronin, Neil
author_facet Romo, Lindsay
Mohn, Emily S.
Aronin, Neil
author_sort Romo, Lindsay
collection PubMed
description Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD.
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spelling pubmed-60048952018-06-25 A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease Romo, Lindsay Mohn, Emily S. Aronin, Neil J Huntingtons Dis Review Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD. IOS Press 2018-06-01 /pmc/articles/PMC6004895/ /pubmed/29865084 http://dx.doi.org/10.3233/JHD-180292 Text en © 2018 – IOS Press and the authors. All rights reserved 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
Romo, Lindsay
Mohn, Emily S.
Aronin, Neil
A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
title A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
title_full A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
title_fullStr A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
title_full_unstemmed A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
title_short A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
title_sort fresh look at huntingtin mrna processing in huntington’s disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004895/
https://www.ncbi.nlm.nih.gov/pubmed/29865084
http://dx.doi.org/10.3233/JHD-180292
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