Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

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 UPR (Unfolded Protein Response) that functions to maintain ER (endoplasmic reticulum) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification (PTM) called Fic-mediated Adenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an AMP (adenosine monophosphate) to the ER chaperone, BiP, to alter the cells UPR-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 Parkinsons disease (PD). Aggregated Syn has been shown to induce ER stress and elicit neurotoxicity in PD models. We show that HYPE adenylylates Syn and reduces phenotypes associated with Syn aggregation in vitro, suggesting a possible mechanism by which cells cope with Syn toxicity.\n\nHIGHLIGHTSO_LIAggregated forms of the presynaptic protein Syn cause neurotoxicity and induce ER stress in cellular and animal models of Parkinsons disease.\nC_LIO_LIWe have identified Syn as a novel target for the human Fic protein, HYPE, a key regulator of ER homeostasis.\nC_LIO_LIHYPE adenylylates Syn and reduces the aggregation of recombinant Syn\nC_LIO_LIFic-mediated adenylylation/AMPylation is a possible mechanism by which cells cope with Syn toxicity.\nC_LI\n\nGraphic Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY