Apr 9, 2020

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

BioRxiv : the Preprint Server for Biology
L. N. PuentesRobert H Mach


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 (Syn) 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 Syn elicits its neurotoxic effects remain unclear. Recent findings indicate that one of the key processes driving PD pathology are oligomeric species of Syn. 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 Syn (pSyn). In this study, we sought to explore how PARP-1 enzymatic product (PAR) drives the conversion of monomeric Syn into aggregated assemblies. Our studies show that elevated intracellular levels of PAR promote the transition of Syn into higher molecular weight forms - including oligomers and pSyn inclusions. Furthermore, quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of -synucleinopathy (M83-SNCA*A53T) and post-mortem PD patient samples, reveal that PAR-pSyn interactions are predominant in path...Continue Reading

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Phylogenetic Analysis
Pharmacologic Substance
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Infectious Agent

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