RT Journal Article
SR Electronic
T1 Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 525659
DO 10.1101/525659
A1 Anwesha Sanyal
A1 Sayan Dutta
A1 Aswathy Chandran
A1 Antonius Koller
A1 Ali Camara
A1 Ben G. Watson
A1 Ranjan Sengupta
A1 Daniel Ysselstein
A1 Paola Montenegro
A1 Jason Cannon
A1 Jean-Christophe Rochet
A1 Seema Mattoo
YR 2019
UL http://biorxiv.org/content/early/2019/01/21/525659.abstract
AB 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 cell’s UPR-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE - alpha-Synuclein (αSyn), a presynaptic protein involved in Parkinson’s disease (PD). Aggregated αSyn has been shown to induce ER stress and elicit neurotoxicity in PD models. We show that HYPE adenylylates αSyn and reduces phenotypes associated with αSyn aggregation in vitro, suggesting a possible mechanism by which cells cope with αSyn toxicity.Aggregated forms of the presynaptic protein αSyn cause neurotoxicity and induce ER stress in cellular and animal models of Parkinson’s disease.We have identified αSyn as a novel target for the human Fic protein, HYPE, a key regulator of ER homeostasis.HYPE adenylylates αSyn and reduces the aggregation of recombinant αSynFic-mediated adenylylation/AMPylation is a possible mechanism by which cells cope with αSyn toxicity.Graphic Abstract AMP:Adenosine monophosphateBiP:Binding immunoglobulin proteinBLI:Biolayer InferometryER:Endoplasmic reticulumFIC:Filamentation induced by cAMPGFP:Green fluorescence proteinGS-AT:Glutamine synthase adenylyltransferaseHYPE:Huntingtin yeast interacting protein ELC-MS:Liquid chromatography – mass spectrometryMAP2:Microtubule associated protein 2NAC:Non-amyloid-beta component of Alzheimer’s diseasePD:Parkinson’s DiseasePTM:Post-translational modificationSUV:Small unilamellar vesiclesTEM:Transmission electron microscopyTH:Tyrosine hydroxylaseUPR:Unfolded protein responseWT:wild type