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bioRxiv · 10.1101/2022.01.06.475207

A novel form of macropinocytosis mediates ultra-rapid transfer of pathological alpha- synuclein to lysosomes

Bayati, A.·Banks, E.·Han, C.·Luo, W.·Zorca, C.·Reintsch, W. E.·Vanderperre, B.·McBride, H. M.·Fon, E. A.·Durcan, T. A.·McPherson, P. S.
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Abstract

The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinsons 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 naive 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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Bayati, A., Banks, E., Han, C., Luo, W., Zorca, C., Reintsch, W. E., Vanderperre, B., McBride, H. M., Fon, E. A., Durcan, T. A., McPherson, P. S.. 2022-01-06. A novel form of macropinocytosis mediates ultra-rapid transfer of pathological alpha- synuclein to lysosomes. https://doi.org/10.1101/2022.01.06.475207

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