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Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans

The societal costs of neurodegenerative diseases demand a sense of urgency and innovative strategies toward therapeutic intervention. We have exploited the experimental attributes of roundworm, C. elegans, as a model to expedite discovery of genetic and chemical modifiers of the age-dependent progre...

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Autor principal: Caldwell, Guy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7742646/
http://dx.doi.org/10.1093/geroni/igaa057.2635
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author Caldwell, Guy
author_facet Caldwell, Guy
author_sort Caldwell, Guy
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description The societal costs of neurodegenerative diseases demand a sense of urgency and innovative strategies toward therapeutic intervention. We have exploited the experimental attributes of roundworm, C. elegans, as a model to expedite discovery of genetic and chemical modifiers of the age-dependent progressive neurodegeneration of dopaminergic neurons commonly associated with Parkinson’s disease (PD). Our model of transgenic nematodes overexpressing the misfolding-prone familial PD gene product, alpha-synuclein, has proven prescient in illuminating key aspects of PD pathology, including vesicular trafficking, autophagy, stress response, lipid dynamics, as well as the first evidence of endolysosomal function in effecting dopaminergic neurodegeneration. Subsequent chemical-genetic analyses reveal a mechanism whereby dopamine transport intersects with epigenetic control of gene expression through proteins functioning in endocytic regulation to modulate neuroprotection. We theorize this reflects a “tunable” nexus of gene-by-environmental regulation where dopamine levels, which impact alpha-synuclein misfolding, are coordinately controlled with epigenetic response to mediate resilience to age-dependent neurodegeneration.
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spelling pubmed-77426462020-12-21 Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans Caldwell, Guy Innov Aging Abstracts The societal costs of neurodegenerative diseases demand a sense of urgency and innovative strategies toward therapeutic intervention. We have exploited the experimental attributes of roundworm, C. elegans, as a model to expedite discovery of genetic and chemical modifiers of the age-dependent progressive neurodegeneration of dopaminergic neurons commonly associated with Parkinson’s disease (PD). Our model of transgenic nematodes overexpressing the misfolding-prone familial PD gene product, alpha-synuclein, has proven prescient in illuminating key aspects of PD pathology, including vesicular trafficking, autophagy, stress response, lipid dynamics, as well as the first evidence of endolysosomal function in effecting dopaminergic neurodegeneration. Subsequent chemical-genetic analyses reveal a mechanism whereby dopamine transport intersects with epigenetic control of gene expression through proteins functioning in endocytic regulation to modulate neuroprotection. We theorize this reflects a “tunable” nexus of gene-by-environmental regulation where dopamine levels, which impact alpha-synuclein misfolding, are coordinately controlled with epigenetic response to mediate resilience to age-dependent neurodegeneration. Oxford University Press 2020-12-16 /pmc/articles/PMC7742646/ http://dx.doi.org/10.1093/geroni/igaa057.2635 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Abstracts
Caldwell, Guy
Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans
title Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans
title_full Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans
title_fullStr Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans
title_full_unstemmed Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans
title_short Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans
title_sort functional modulators of resilience to age-associated dopaminergic neurodegeneration in c. elegans
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7742646/
http://dx.doi.org/10.1093/geroni/igaa057.2635
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