PARylation in Parkinson’s disease: a bridge between Lewy body formation and neuronal cell death

Poly-ADP-ribosylation (PARylation), catalyzed by the enzyme PARP1, involves the addition of poly-ADP-ribose polymers (PAR) and has been associated with α-synuclein aggregation in Parkinson's disease (PD) models. This study aimed to unravel the role of PARylation in α-synuclein aggregation and neuronal cell death in the complex environment of post-mortem human PD brains. Using high-resolution imaging and 3D reconstruction analysis, we observed that PAR accumulate in the cytoplasm in regions affected by PD pathology, preceding the formation of α-synuclein oligomers. Additionally, we found that PAR and stress granules contribute to the formation of Lewy bodies. Increased colocalization of PAR with mitochondria in the substantia nigra of PD patients, along with the presence of PAR-positive condensed DNA, further suggests a role in neuronal cell death. Collectively, our findings reveal a critical involvement of PARylation in the pathological mechanisms underlying neurodegeneration in PD and position PARylation as a potential therapeutic target.