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Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity

Rachel Underwood, Bing Wang, Aneesh Pathak, Laura Volpicelli-Daley, Talene A. Yacoubian
doi: https://doi.org/10.1101/2020.11.17.387449
Rachel Underwood
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Bing Wang
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Aneesh Pathak
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Laura Volpicelli-Daley
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Talene A. Yacoubian
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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  • For correspondence: tyacoubian@uabmc.edu
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SUMMARY

Parkinson’s disease and Dementia with Lewy Bodies are two common neurodegenerative disorders marked by proteinaceous aggregates composed primarily of the protein α-synuclein. α-Synuclein is hypothesized to have prion-like properties, by which misfolded α-synuclein induces the pathological aggregation of endogenous α-synuclein and neuronal loss. Rab27a and Rab27b are two highly homologous Rab GTPases that regulate α-synuclein secretion, clearance, and toxicity in vitro. In this study, we tested the impact of Rab27a/b on the transmission of pathogenic α-synuclein. Double knockout of both Rab27 isoforms eliminated α-synuclein aggregation and neuronal toxicity in primary cultured neurons exposed to fibrillary α-synuclein. In vivo, Rab27 double knockout mice lacked fibril-induced α-synuclein inclusions, dopaminergic neuron loss, and behavioral deficits seen in wildtype mice with fibril-induced inclusions. Studies using AlexaFluor488-labeled α-synuclein fibrils revealed that Rab27a/b knockout prevented α-synuclein internalization without affecting bulk endocytosis. Rab27a/b knockout also blocked the cell-to-cell spread of α-synuclein pathology in multifluidic, multichambered devices. This study provides critical insight into the role of Rab GTPases in Parkinson’s disease and identifies Rab27s as key players in the progression of synucleinopathies.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 17, 2020.
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Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity
Rachel Underwood, Bing Wang, Aneesh Pathak, Laura Volpicelli-Daley, Talene A. Yacoubian
bioRxiv 2020.11.17.387449; doi: https://doi.org/10.1101/2020.11.17.387449
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Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity
Rachel Underwood, Bing Wang, Aneesh Pathak, Laura Volpicelli-Daley, Talene A. Yacoubian
bioRxiv 2020.11.17.387449; doi: https://doi.org/10.1101/2020.11.17.387449

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