Impaired endo-lysosomal membrane integrity accelerates the seeding progression of ?-synuclein aggregates.

ABSTRACT: In neurodegenerative diseases, seeding is a process initiated by the internalization of exogenous protein aggregates. Multiple pathways for internalization of aggregates have been proposed, including direct membrane penetration and endocytosis. To decipher the seeding mechanisms of alpha-synuclein (?S) aggregates in human cells, we visualized ?S aggregation, endo-lysosome distribution, and endo-lysosome rupture in real-time. Our data suggest that exogenous ?S can seed endogenous cytoplasmic ?S by either directly penetrating the plasma membrane or via endocytosis-mediated endo-lysosome rupture, leading to formation of endo-lysosome-free or endo-lysosome-associated ?S aggregates, respectively. Further, we demonstrate that ?S aggregates isolated from postmortem human brains with diffuse Lewy body disease (DLBD) preferentially show endocytosis-mediated seeding associated with endo-lysosome rupture and have significantly reduced seeding activity compared to recombinant ?S aggregates. Colocalization of ?S pathology with galectin-3 (a marker of endo-lysosomal membrane rupture) in the basal forebrain of DLBD, but not in age-matched controls, suggests endo-lysosome rupture is involved in the formation of ?S pathology in humans. Interestingly, cells with endo-lysosomal membrane permeabilization (LMP) are more vulnerable to the seeding effects of ?S aggregates. This study suggests that endo-lysosomal impairment in neurons might play an important role in PD progression.

SUBMITTER: Jiang P 

PROVIDER: S-EPMC5550496 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature