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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...

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Autores principales: Carnwath, Tom, Mohammed, Raihan, Tsiang, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
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.
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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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