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The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease

Authors Carnwath T, Mohammed R, Tsiang D

Received 23 February 2018

Accepted for publication 3 April 2018

Published 27 June 2018 Volume 2018:14 Pages 1685—1695


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Roger Pinder

Tom Carnwath,1 Raihan Mohammed,2 Daniel Tsiang3

1Department of Zoology, University of Cambridge, Cambridge, UK; 2Faculty of Medicine, University of Cambridge, Cambridge, UK; 3Faculty of Engineering, Imperial College London, London, UK

Abstract: 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.

Keywords: tubulin, tau, axon, phosphorylation, Alzheimer’s disease

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