The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins

Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine...

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Autores principales:	Austin Folger, Yanchang Wang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	protein misfolding mutated Huntingtin ubiquitin-proteasome system (UPS) Cdc48 autophagy Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/37ae36b92d884b0494124a943a5f326f
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spelling	oai:doaj.org-article:37ae36b92d884b0494124a943a5f326f2021-11-25T17:07:44ZThe Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins10.3390/cells101128352073-4409https://doaj.org/article/37ae36b92d884b0494124a943a5f326f2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2835https://doaj.org/toc/2073-4409Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.Austin FolgerYanchang WangMDPI AGarticleprotein misfoldingmutated Huntingtinubiquitin-proteasome system (UPS)Cdc48autophagyBiology (General)QH301-705.5ENCells, Vol 10, Iss 2835, p 2835 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	protein misfolding mutated Huntingtin ubiquitin-proteasome system (UPS) Cdc48 autophagy Biology (General) QH301-705.5
spellingShingle	protein misfolding mutated Huntingtin ubiquitin-proteasome system (UPS) Cdc48 autophagy Biology (General) QH301-705.5 Austin Folger Yanchang Wang The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
description	Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.
format	article
author	Austin Folger Yanchang Wang
author_facet	Austin Folger Yanchang Wang
author_sort	Austin Folger
title	The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
title_short	The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
title_full	The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
title_fullStr	The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
title_full_unstemmed	The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins
title_sort	cytotoxicity and clearance of mutant huntingtin and other misfolded proteins
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/37ae36b92d884b0494124a943a5f326f
work_keys_str_mv	AT austinfolger thecytotoxicityandclearanceofmutanthuntingtinandothermisfoldedproteins AT yanchangwang thecytotoxicityandclearanceofmutanthuntingtinandothermisfoldedproteins AT austinfolger cytotoxicityandclearanceofmutanthuntingtinandothermisfoldedproteins AT yanchangwang cytotoxicityandclearanceofmutanthuntingtinandothermisfoldedproteins
_version_	1718412706812264448

The Cytotoxicity and Clearance of Mutant Huntingtin and Other Misfolded Proteins

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