Rapid macropinocytic transfer of α-synuclein to lysosomes

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

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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Please see paper on Cell Reports for detailed methods.

Institutions

McGill University, Montreal Neurological Institute and Hospital

Categories

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

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