PT  - JOURNAL ARTICLE
AU  - Meraj Ramezani
AU  - Marcus M. Wilkes
AU  - Tapojyoti Das
AU  - David Holowka
AU  - David Eliezer
AU  - Barbara Baird
TI  - Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model
AID  - 10.1101/492066
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 492066
4099  - http://biorxiv.org/content/early/2018/12/10/492066.short
4100  - http://biorxiv.org/content/early/2018/12/10/492066.full
AB  - We characterized phenotypes in RBL-2H3 mast cells transfected with human alpha synuclein (a-syn) using stimulated exocytosis of recycling endosomes as a proxy for similar activities of synaptic vesicles in neurons. We found that low expression of a-syn inhibits stimulated exocytosis and that higher expression causes slight enhancement. NMR measurements of membrane interactions correlate with these functional effects: they are eliminated differentially by mutants that perturb helical structure in the helix 1 (A30P) or NAC/helix-2 (V70P) regions of membrane-bound a-syn, but not by other PD-associated mutants or C-terminal truncation. We further found that a-syn (but not A30P or V70P mutants) associates weakly with mitochondria, but this association increases markedly under conditions of cellular stress. These results highlight the importance of specific structural features of a-syn in regulating vesicle release, and point to a potential role for a-syn in perturbing mitochondrial function under pathological conditions.