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Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila
Leucine-rich repeat kinase 2 (LRRK2) is a complex protein kinase involved in a diverse set of functions. Mutations in LRRK2 are a common cause of autosomal dominant familial Parkinson’s disease. Peroxiredoxin 2 (PRDX2) belongs to a family of anti-oxidants that protect cells from oxidative stress. Im...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585092/ https://www.ncbi.nlm.nih.gov/pubmed/32990658 http://dx.doi.org/10.18632/aging.103843 |
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author | Chua, Ling Ling Ho, Patrick Toh, Joanne Tan, Eng-King |
author_facet | Chua, Ling Ling Ho, Patrick Toh, Joanne Tan, Eng-King |
author_sort | Chua, Ling Ling |
collection | PubMed |
description | Leucine-rich repeat kinase 2 (LRRK2) is a complex protein kinase involved in a diverse set of functions. Mutations in LRRK2 are a common cause of autosomal dominant familial Parkinson’s disease. Peroxiredoxin 2 (PRDX2) belongs to a family of anti-oxidants that protect cells from oxidative stress. Importantly, PRDX2 is a cytoplasmic protein, similar to Leucine-rich repeat kinase 2, which localizes predominantly in the cytosol. Here, we demonstrated that Leurice-rich repeat kinase 2 phosphorylates PRDX2 in Drosophila, leading to a loss of dopaminergic neurons, climbing ability and shortened lifespan. These pathogenic phenotypes in the LRRK2 Drosophila were rescued with transgenic expression of PRDX2. Chetomin, a PRDX2 mimic, belongs to a class of epidithio-diketopiperazine fungal secondary metabolites (containing a dithiol group that has hydrogen peroxide-reducing activity). As proof of principle, we demonstrated that Chetomin recapitulated the rescue in these mutant Drosophila. Our findings suggest that Chetomin can be a potential therapeutic compound in LRRK2 linked Parkinson’s disease. |
format | Online Article Text |
id | pubmed-7585092 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-75850922020-11-03 Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila Chua, Ling Ling Ho, Patrick Toh, Joanne Tan, Eng-King Aging (Albany NY) Research Paper Leucine-rich repeat kinase 2 (LRRK2) is a complex protein kinase involved in a diverse set of functions. Mutations in LRRK2 are a common cause of autosomal dominant familial Parkinson’s disease. Peroxiredoxin 2 (PRDX2) belongs to a family of anti-oxidants that protect cells from oxidative stress. Importantly, PRDX2 is a cytoplasmic protein, similar to Leucine-rich repeat kinase 2, which localizes predominantly in the cytosol. Here, we demonstrated that Leurice-rich repeat kinase 2 phosphorylates PRDX2 in Drosophila, leading to a loss of dopaminergic neurons, climbing ability and shortened lifespan. These pathogenic phenotypes in the LRRK2 Drosophila were rescued with transgenic expression of PRDX2. Chetomin, a PRDX2 mimic, belongs to a class of epidithio-diketopiperazine fungal secondary metabolites (containing a dithiol group that has hydrogen peroxide-reducing activity). As proof of principle, we demonstrated that Chetomin recapitulated the rescue in these mutant Drosophila. Our findings suggest that Chetomin can be a potential therapeutic compound in LRRK2 linked Parkinson’s disease. Impact Journals 2020-09-24 /pmc/articles/PMC7585092/ /pubmed/32990658 http://dx.doi.org/10.18632/aging.103843 Text en Copyright: © 2020 Chua et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Chua, Ling Ling Ho, Patrick Toh, Joanne Tan, Eng-King Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila |
title | Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila |
title_full | Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila |
title_fullStr | Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila |
title_full_unstemmed | Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila |
title_short | Chetomin rescues pathogenic phenotype of LRRK2 mutation in drosophila |
title_sort | chetomin rescues pathogenic phenotype of lrrk2 mutation in drosophila |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585092/ https://www.ncbi.nlm.nih.gov/pubmed/32990658 http://dx.doi.org/10.18632/aging.103843 |
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