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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Published inFrontiers in molecular biosciences Vol. 8; p. 769184
Main Authors Jarosińska, Olga D., Rüdiger, Stefan G. D.
Format Journal Article
LanguageEnglish
Published Frontiers Media S.A 12.11.2021
Subjects
aggregation
huntingtin (HTT)
Molecular Biosciences
protein degradation
protein fibrils
protein quality control
proteostasis
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Summary: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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Edited by: Walid A Houry, University of Toronto, Canada
Stefan Rüdiger
ORCID
Reviewed by: Swasti Raychaudhuri, Centre for Cellular and Molecular Biology (CCMB), India
Axel Mogk, Heidelberg University, Germany
Olga Jarosińska
0000-0002-2184-3993
This article was submitted to Protein Folding, Misfolding and Degradation, a section of the journal Frontiers in Molecular Biosciences
0000-0002-1807-2972
ISSN:2296-889X
2296-889X
DOI:10.3389/fmolb.2021.769184