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 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

Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review

“…Collectively, acetylation of the N-terminal region of α-synuclein reduced aggregation in four out of five studies [123][124][125][126], and with one study that reported that this PTM increased the propensity of α-synuclein to aggregate [127]. Adenylylation at T33, T54, and T75 reduced α-synuclein aggregation [128]. Glycation at multiple lysine residues increased α-synuclein aggregation and formation of stable oligomers [129].…”

A Pronucleotide Probe for Live‐Cell Imaging of Protein AMPylation

“…Protein AMPylation is a highly abundant post‐translational modification (PTM) regulating unfolded protein response (UPR), differentiation of neural progenitors and α‐synuclein modification . AMPylation is catalyzed by AMP transferases (AMPylators), which transfer adenosine 5′‐ O ‐monophosphate from substrate ATP onto Ser, Thr or Tyr residues in target proteins (Scheme A) .…”

Cellular microbiology: Bacterial toxin interference drives understanding of eukaryotic cell function

“…Parkinson's disease(Sanyal et al, 2019). This demonstrates again how cellular microbiology contributes to a better understanding of a broad number of human diseases.…”

“…This involves an allosteric‐based AMPylation‐competent recruitment of Mg‐ATP. Recent findings have shown that huntingtin yeast‐interacting protein E stimulates the alpha‐synuclein, thereby preventing its aggregation, a neuroprotective response that could be exploited in the treatment of Parkinson's disease (Sanyal et al, ). This demonstrates again how cellular microbiology contributes to a better understanding of a broad number of human diseases.…”