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

Abstract

SUMMARYParkinson’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.

Rapid macropinocytic transfer of α-synuclein to lysosomes

“…Our findings point to the endocytosis of PFF through a form of macropinocytosis, where macropinosomes either mature into MVBs and lysosomes or fuse with preexisting LAMP1 + compartments (i.e., late endosomes and lysosomes). Recent papers show promising results regarding the role of actin in PFF internalization (Underwood et al, 2020;Zhang et al, 2020).…”

Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

“…Rab27b regulates translocation of late endosomes to the cell periphery and their exocytosis 73 , and was recently shown to be transcriptionally regulated by the cytoprotective transcription factor Nrf2 74 . In Parkinson’s disease, higher expression of Rab27b has been reported in patient brain samples 75 , where it may promote the cell-to-cell transmission of pathogenic alpha-synuclein aggregates through a lysosomal exocytosis and re-uptake mechanism 75, 76 . We validated the increase and rescue of Rab27b in VPS35 KO cells by Western blotting of whole cell lysate and lysosome immunoprecipitates ( Figs.…”

Rapid macropinocytic transfer of α-synuclein to lysosomes

“…Our findings point to PFF endocytosis using a novel form of macropinocytosis, where macropinosomes either mature into MVBs and lysosomes or fuse with pre-existing LAMP1- positive compartments. Recent papers show promising results regarding the role of actin in PFF internalization (Underwood et al, 2020; Zhang et al, 2020).…”