Constitutive Endolysosomal Perforation in Neurons allows Induction of α-Synuclein Aggregation by Internalized Pre-Formed Fibrils.

ABSTRACT: The endocytic pathway is both an essential route of molecular uptake in cells and a potential entry point for pathology-inducing cargo. The cell-to-cell spread of cytotoxic aggregates, such as those of α-synuclein (α-syn) in Parkinson's Disease (PD), exemplifies this duality. Here we used a human iPSC-derived induced neuronal model (iNs) prone to death mediated by aggregation in late endosomes and lysosomes of endogenous α-syn, seeded by internalized pre-formed fibrils of α-syn (PFFs). This PFF-mediated death was not observed with parental iPSCs or other non-neuronal cells. Using live-cell optical microscopy to visualize the read out of biosensors reporting endo-lysosome wounding, we discovered that up to about 10% of late endosomes and lysosomes in iNs exhibited spontaneous constitutive p

SUBMITTER: Sanyal A 

PROVIDER: S-EPMC10802249 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature