Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson's Disease.

ABSTRACT: During disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called unfolded protein response that functions to maintain endoplasmic reticulum (ER) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification called Fic-mediatedadenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an adenosine monophosphate (AMP) to the ER chaperone, BiP, to alter the cell's unfolded protein response-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE-alpha-synuclein (?Syn), a presynaptic protein involved in Parkinson's disease. Aggregated ?Syn has been shown to induce ER stress and elicit neurotoxicity in Parkinson's disease models. We show that HYPE adenylylates ?Syn and reduces phenotypes associated with ?Syn aggregation invitro, suggesting a possible mechanism by which cells cope with ?Syn toxicity.

SUBMITTER: Sanyal A 

PROVIDER: S-EPMC6554060 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature