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Poly (ADP-ribose) induces α-synuclein aggregation in neuronal-like cells and interacts with phosphorylated α-synuclein in post mortem PD samples

Background Poly (ADP-ribose) (PAR) is a negatively charged polymer that is biosynthesized by Poly (ADP-ribose) Polymerase-1 (PARP-1) and regulates various cellular processes. Alpha-synuclein (αSyn) is an intrinsically disordered protein (IDP) that has been directly implicated with driving the onset and progression of Parkinson’s disease (PD). The mechanisms by which αSyn elicits its neurotoxic effects remain unclear. Recent findings indicate that one of the key processes driving PD pathology are oligomeric species of αSyn. Furthermore, it is well established that the main components of Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients are aggregated hyperphosphorylated (S129) forms of αSyn (pαSyn). Methods We used biochemical and immunofluorescence-based assays to explore if PARP-1 enzymatic product (PAR) drives the conversion of monomeric αSyn into aggregated assemblies. We performed quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of α-synucleinopathy (M83-SNCA*A53T) and post-mortem PD/PDD patient samples to characterize PAR-pαSyn interactions. Additionally, we used bioinformatic approaches and site-directed mutagenesis to identify PAR-binding regions on fibrillar αSyn. Results Our studies show that elevated intracellular levels of PAR promote the transition of αSyn into higher molecular weight forms. We report that PAR-pαSyn interactions are predominant in pathological states. Moreover, we confirm that the interactions between PAR and αSyn involve electrostatic forces between negatively charged PAR and lysine residues on the N-terminal region of αSyn. Conclusions PAR plays a critical role in the early stages of monomeric αSyn aggregation, thereby attributing to PD pathogenesis. Based on our results, we report that PAR seeds monomeric αSyn aggregation and directly interacts with phosphorylated αSyn in conditions that are pathologically relevant to PD.