The Localization of Alpha-synuclein in the Endocytic Pathway

Alpha-synuclein (alpha S) is an intrinsically disordered protein (IDP) that is abundantly present in the brain and is associated with Parkinson's disease (PD). In spite of its abundance and its contribution to PD pathogenesis, the exact cellular function of alpha S remains largely unknown. The ability of alpha S to remodel phospholipid model membranes combined with biochemical and cellular studies suggests that alpha S is involved in endocytosis. To unravel with which route(s) and stage(s) of the endocytic pathway alpha S is associated, we quantified the colocalization between alpha S and endocytic marker proteins in differentiated SH-SY5Y neuronal cells, using an object based colocalization analysis. Comparison with randomized data allowed us to discriminate between structural and coincidental colocalizations. A large fraction of the alpha S positive vesicles colocalizes with caveolin positive vesicles, a smaller fraction colocalizes with EEA1 and Rab7. We find no structural colocalization between alpha S and clathrin and Rab11 positive vesicles. We conclude that in a physiological context, alpha S is structurally associated with caveolin dependent membrane vesiculation and is found further along the endocytic pathway, in decreasing amounts, on early and late endosomes. Our results not only shed new light on the function of alpha S, they also provide a possible link between alpha S function and vesicle trafficking malfunction in PD. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of IBRO.

Automated summary

This study reveals the relationship between alpha-synuclein and the endocytic pathway, showing a structural association of alpha S with caveolin-dependent membrane vesiculation further along the endocytic pathway, possibly linking alpha S function to vesicle trafficking dysfunction in Parkinson's disease.