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Rapid macropinocytic transfer of α-synuclein to lysosomes.
- Source :
-
Cell reports [Cell Rep] 2022 Jul 19; Vol. 40 (3), pp. 111102. - Publication Year :
- 2022
-
Abstract
- The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinson's disease (PD) and other synucleinopathies; however, the mechanisms underlying internalization and cellular spread are enigmatic. Here, we use confocal and superresolution microscopy, subcellular fractionation, and electron microscopy (EM) of immunogold-labeled α-synuclein preformed fibrils (PFFs) to demonstrate that this form of the protein undergoes rapid internalization and is targeted directly to lysosomes in as little as 2 min. Uptake of PFFs is disrupted by macropinocytic inhibitors and circumvents classical endosomal pathways. Immunogold-labeled PFFs 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 naive cells along with markers of exosomes. These data indicate that PFFs use a unique internalization mechanism as a component of cell-to-cell propagation.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 40
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 35858558
- Full Text :
- https://doi.org/10.1016/j.celrep.2022.111102