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Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

Huntington’s disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and u...

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Autores principales: Jarosińska, Olga D., Rüdiger, Stefan G. D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636123/
https://www.ncbi.nlm.nih.gov/pubmed/34869596
http://dx.doi.org/10.3389/fmolb.2021.769184
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author Jarosińska, Olga D.
Rüdiger, Stefan G. D.
author_facet Jarosińska, Olga D.
Rüdiger, Stefan G. D.
author_sort Jarosińska, Olga D.
collection PubMed
description Huntington’s disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and ultimately cell death. There are currently still no treatments available for HD, but approaches targeting the HTT levels offer systematic, mechanism-driven routes towards curing HD and other neurodegenerative diseases. This review summarizes the current state of knowledge of the mRNA targeting approaches such as antisense oligonucleotides and RNAi system; and the novel methods targeting mHTT and aggregates for degradation via the ubiquitin proteasome or the autophagy-lysosomal systems. These methods include the proteolysis-targeting chimera, Trim-Away, autophagosome-tethering compound, autophagy-targeting chimera, lysosome-targeting chimera and approach targeting mHTT for chaperone-mediated autophagy. These molecular strategies provide a knowledge-based approach to target HD and other neurodegenerative diseases at the origin.
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spelling pubmed-86361232021-12-02 Molecular Strategies to Target Protein Aggregation in Huntington’s Disease Jarosińska, Olga D. Rüdiger, Stefan G. D. Front Mol Biosci Molecular Biosciences Huntington’s disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and ultimately cell death. There are currently still no treatments available for HD, but approaches targeting the HTT levels offer systematic, mechanism-driven routes towards curing HD and other neurodegenerative diseases. This review summarizes the current state of knowledge of the mRNA targeting approaches such as antisense oligonucleotides and RNAi system; and the novel methods targeting mHTT and aggregates for degradation via the ubiquitin proteasome or the autophagy-lysosomal systems. These methods include the proteolysis-targeting chimera, Trim-Away, autophagosome-tethering compound, autophagy-targeting chimera, lysosome-targeting chimera and approach targeting mHTT for chaperone-mediated autophagy. These molecular strategies provide a knowledge-based approach to target HD and other neurodegenerative diseases at the origin. Frontiers Media S.A. 2021-11-12 /pmc/articles/PMC8636123/ /pubmed/34869596 http://dx.doi.org/10.3389/fmolb.2021.769184 Text en Copyright © 2021 Jarosińska and Rüdiger. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Jarosińska, Olga D.
Rüdiger, Stefan G. D.
Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
title Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
title_full Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
title_fullStr Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
title_full_unstemmed Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
title_short Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
title_sort molecular strategies to target protein aggregation in huntington’s disease
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636123/
https://www.ncbi.nlm.nih.gov/pubmed/34869596
http://dx.doi.org/10.3389/fmolb.2021.769184
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