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Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?
At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyl...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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SAGE Publications
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102758/ https://www.ncbi.nlm.nih.gov/pubmed/30147359 http://dx.doi.org/10.1177/1179069518794675 |
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author | Smith, David M |
author_facet | Smith, David M |
author_sort | Smith, David M |
collection | PubMed |
description | At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell’s protein degradation system for individual proteins—the ubiquitin proteasome system (UPS)—does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein’s primary amino acid sequence was irrelevant to its ability to inhibit. Instead, the culprit is the 3-dimensional shape of the misfolded oligomers. It turns out that many misfolded proteins in ND can take on this proteasome-impairing shape suggesting that there could be a common mechanism for UPS impairment in many NDs. The proteasome is already an important target for treating cancer, could it also be targeted to broadly treat ND? |
format | Online Article Text |
id | pubmed-6102758 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-61027582018-08-24 Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases? Smith, David M J Exp Neurosci Commentary At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell’s protein degradation system for individual proteins—the ubiquitin proteasome system (UPS)—does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein’s primary amino acid sequence was irrelevant to its ability to inhibit. Instead, the culprit is the 3-dimensional shape of the misfolded oligomers. It turns out that many misfolded proteins in ND can take on this proteasome-impairing shape suggesting that there could be a common mechanism for UPS impairment in many NDs. The proteasome is already an important target for treating cancer, could it also be targeted to broadly treat ND? SAGE Publications 2018-08-19 /pmc/articles/PMC6102758/ /pubmed/30147359 http://dx.doi.org/10.1177/1179069518794675 Text en © The Author(s) 2018 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Commentary Smith, David M Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases? |
title | Could a Common Mechanism of Protein Degradation Impairment Underlie
Many Neurodegenerative Diseases? |
title_full | Could a Common Mechanism of Protein Degradation Impairment Underlie
Many Neurodegenerative Diseases? |
title_fullStr | Could a Common Mechanism of Protein Degradation Impairment Underlie
Many Neurodegenerative Diseases? |
title_full_unstemmed | Could a Common Mechanism of Protein Degradation Impairment Underlie
Many Neurodegenerative Diseases? |
title_short | Could a Common Mechanism of Protein Degradation Impairment Underlie
Many Neurodegenerative Diseases? |
title_sort | could a common mechanism of protein degradation impairment underlie
many neurodegenerative diseases? |
topic | Commentary |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102758/ https://www.ncbi.nlm.nih.gov/pubmed/30147359 http://dx.doi.org/10.1177/1179069518794675 |
work_keys_str_mv | AT smithdavidm couldacommonmechanismofproteindegradationimpairmentunderliemanyneurodegenerativediseases |