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Engineering therapeutic protein disaggregases
Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfol...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865313/ https://www.ncbi.nlm.nih.gov/pubmed/27255695 http://dx.doi.org/10.1091/mbc.E15-10-0693 |
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author | Shorter, James |
author_facet | Shorter, James |
author_sort | Shorter, James |
collection | PubMed |
description | Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD. |
format | Online Article Text |
id | pubmed-4865313 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-48653132016-07-30 Engineering therapeutic protein disaggregases Shorter, James Mol Biol Cell MBoC Perspective on Cell Biology and Human Health Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD. The American Society for Cell Biology 2016-05-15 /pmc/articles/PMC4865313/ /pubmed/27255695 http://dx.doi.org/10.1091/mbc.E15-10-0693 Text en © 2016 Shorter. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | MBoC Perspective on Cell Biology and Human Health Shorter, James Engineering therapeutic protein disaggregases |
title | Engineering therapeutic protein disaggregases |
title_full | Engineering therapeutic protein disaggregases |
title_fullStr | Engineering therapeutic protein disaggregases |
title_full_unstemmed | Engineering therapeutic protein disaggregases |
title_short | Engineering therapeutic protein disaggregases |
title_sort | engineering therapeutic protein disaggregases |
topic | MBoC Perspective on Cell Biology and Human Health |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865313/ https://www.ncbi.nlm.nih.gov/pubmed/27255695 http://dx.doi.org/10.1091/mbc.E15-10-0693 |
work_keys_str_mv | AT shorterjames engineeringtherapeuticproteindisaggregases |