PARIS undergoes liquid–liquid phase separation and poly(ADP‐ribose)‐mediated solidification

Abstract

AbstractZNF746 was identified as parkin‐interacting substrate (PARIS). Investigating its pathophysiological properties, we find that PARIS undergoes liquid–liquid phase separation (LLPS) and amorphous solid formation. The N‐terminal low complexity domain 1 (LCD1) of PARIS is required for LLPS, whereas the C‐terminal prion‐like domain (PrLD) drives the transition from liquid to solid phase. In addition, we observe that poly(ADP‐ribose) (PAR) strongly binds to the C‐terminus of PARIS near the PrLD, accelerating its LLPS and solidification. N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG)‐induced PAR formation leads to PARIS oligomerization in human iPSC‐derived dopaminergic neurons that is prevented by the PARP inhibitor, ABT‐888. Furthermore, SDS‐resistant PARIS species are observed in the substantia nigra (SN) of aged mice overexpressing wild‐type PARIS, but not with a PAR binding‐deficient PARIS mutant. PARIS solidification is also found in the SN of mice injected with preformed fibrils of α‐synuclein (α‐syn PFF) and adult mice with a conditional knockout (KO) of parkin, but not if α‐syn PFF is injected into mice deficient for PARP1. Herein, we demonstrate that PARIS undergoes LLPS and PAR‐mediated solidification in models of Parkinson's disease.