RT Journal Article
SR Electronic
T1 Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.17.387449
DO 10.1101/2020.11.17.387449
A1 Rachel Underwood
A1 Bing Wang
A1 Aneesh Pathak
A1 Laura Volpicelli-Daley
A1 Talene A. Yacoubian
YR 2020
UL http://biorxiv.org/content/early/2020/11/17/2020.11.17.387449.abstract
AB 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 StatementThe authors have declared no competing interest.