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The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease
Despite decades of research, the mechanism of Parkinson’s disease pathogenesis remains unclear. Studies have focused heavily on the protein α-synuclein, which is the primary component of Lewy bodies, the pathologic inclusions that are the hallmark of Parkinson’s on the cellular level. While the role...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027679/ https://www.ncbi.nlm.nih.gov/pubmed/29983568 http://dx.doi.org/10.2147/NDT.S166322 |
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author | Carnwath, Tom Mohammed, Raihan Tsiang, Daniel |
author_facet | Carnwath, Tom Mohammed, Raihan Tsiang, Daniel |
author_sort | Carnwath, Tom |
collection | PubMed |
description | Despite decades of research, the mechanism of Parkinson’s disease pathogenesis remains unclear. Studies have focused heavily on the protein α-synuclein, which is the primary component of Lewy bodies, the pathologic inclusions that are the hallmark of Parkinson’s on the cellular level. While the roles of α-synuclein in causing mitochondrial dysfunction and disruptions to the proteasomal system have been well documented, recently, its role in effecting microtubule dynamics has been investigated as a potential source of pathogenicity. Here, we evaluate the evidence for and against the role of α-synuclein in destabilizing microtubules, causing axonal transport deficits and eventually neurodegeneration. We present evidence for a model where α-synuclein has both a direct and indirect effect on microtubule stability. Directly, it may act as a microtubule-associated protein, binding to microtubules and directly effecting their dynamics. Indirectly, it may promote the hyperphosphorylation of the microtubule stabilizing protein, tau, leading to tau aggregation with other microtubule stabilizing proteins, hence indirectly causing microtubule destabilization. This model provides insights into the function of α-synuclein and tau in Parkinson’s disease pathogenesis and raises the possibility that this role that may also be conserved in Alzheimer’s disease. |
format | Online Article Text |
id | pubmed-6027679 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-60276792018-07-06 The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease Carnwath, Tom Mohammed, Raihan Tsiang, Daniel Neuropsychiatr Dis Treat Review Despite decades of research, the mechanism of Parkinson’s disease pathogenesis remains unclear. Studies have focused heavily on the protein α-synuclein, which is the primary component of Lewy bodies, the pathologic inclusions that are the hallmark of Parkinson’s on the cellular level. While the roles of α-synuclein in causing mitochondrial dysfunction and disruptions to the proteasomal system have been well documented, recently, its role in effecting microtubule dynamics has been investigated as a potential source of pathogenicity. Here, we evaluate the evidence for and against the role of α-synuclein in destabilizing microtubules, causing axonal transport deficits and eventually neurodegeneration. We present evidence for a model where α-synuclein has both a direct and indirect effect on microtubule stability. Directly, it may act as a microtubule-associated protein, binding to microtubules and directly effecting their dynamics. Indirectly, it may promote the hyperphosphorylation of the microtubule stabilizing protein, tau, leading to tau aggregation with other microtubule stabilizing proteins, hence indirectly causing microtubule destabilization. This model provides insights into the function of α-synuclein and tau in Parkinson’s disease pathogenesis and raises the possibility that this role that may also be conserved in Alzheimer’s disease. Dove Medical Press 2018-06-27 /pmc/articles/PMC6027679/ /pubmed/29983568 http://dx.doi.org/10.2147/NDT.S166322 Text en © 2018 Carnwath et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Review Carnwath, Tom Mohammed, Raihan Tsiang, Daniel The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease |
title | The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease |
title_full | The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease |
title_fullStr | The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease |
title_full_unstemmed | The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease |
title_short | The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease |
title_sort | direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of parkinson’s disease |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027679/ https://www.ncbi.nlm.nih.gov/pubmed/29983568 http://dx.doi.org/10.2147/NDT.S166322 |
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