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

Laura N Puentes, Zsofia Lengyel-Zhand, Ji Youn Lee, Chia-Ju Hsieh, Mark E Schneider Jr., Kimberly J Edwards, Kelvin C Luk, Virginia M.-Y Lee, John Q Trojanowski, Robert H Mach

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Received Date: 23rd March 20

Poly(ADP-ribose) 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). In this study, we sought to explore how PARP-1 enzymatic product (PAR) drives the conversion of monomeric αSyn into aggregated assemblies. Our studies show that elevated intracellular levels of PAR promote the transition of αSyn into higher molecular weight forms – including oligomers and pαSyn inclusions. Furthermore, quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of α-synucleopathy (M83-SNCA*A53T) and post-mortem PD patient samples, reveal that PAR-pαSyn interactions are predominant in pathological states. In addition, 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. Altogether, our findings reveal that PAR plays a critical role in the early stages of monomeric αSyn aggregation, thereby attributing to PD pathogenesis.

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