Rapid macropinocytic transfer of α-synuclein to lysosomes

Published: 4 July 2022| Version 4 | DOI: 10.17632/nh3cvm3m3p.4


The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinson’s disease (PD) and other synucleinopathies, yet the mechanisms underlying internalization and cellular spread are enigmatic. Here we use confocal and super-resolution microscopy, subcellular fractionation and electron microscopy (EM) of immunogold labelled alpha-synuclein preformed fibrils (PFF) to demonstrate that this fibril form of alpha-synuclein undergoes rapid internalization and is targeted directly to lysosomes in as little as 2 minutes. Uptake of PFF is disrupted by macropinocytic inhibitors and circumvents classical endosomal pathways. Immunogold-labelled PFF are seen at the highly curved inward edge of membrane ruffles, in newly formed macropinosomes, in multivesicular bodies and in lysosomes. While most fibrils remain in lysosomes, a portion is transferred to neighboring naïve cells along with markers of exosomes. These data indicate that PFF use a unique internalization mechanism as a component of cell-to-cell propagation.


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McGill University, Montreal Neurological Institute and Hospital


Cell Biology, Endocytosis in Neurons, Endocytosis, Intracellular Trafficking, Pathology of Parkinson's Disease, Cellular Neuroscience, Exosome