What Is the Potential Role of Poly(ADP-Ribose) Polymerase 1 in Parkinson Disease?

Abstract

Poly(ADP-ribose) (PAR) polymerase 1 (PARP-1) is an enzyme primarily activated in response to DNA damage and modifies proteins by a process known as PARylation. PARP-1 has a major role in DNA damage repair and participates in several cellular processes, including regulation of chromatin structure, transcriptional machinery, RNA processing, and energy metabolism 1-3 PARP-1 participates in a nuclear–mitochondrial crosstalk that is critical for the maintenance of mitochondrial health.4,5 Studies in experimental models indicate that PARP-1 overactivation is associated with cell death in neurologic disorders due to ischemia, neuroinflammation, and neurodegeneration.5-11 PARP-1 overactivation triggers a unique form of programmed cell death known as parthanatos (PARP-1–dependent cell death). One neurodegenerative disorder associated with PARP-1 overactivation is Parkinson disease (PD). A pivotal study showed that recombinant α-synuclein (α-Syn) fibrils promote neuronal death both in vitro and in vivo via activation of PARP-1, and that PARylation accelerates α-Syn fibrillization converting α-Syn fibrils to a more toxic strain, thus establishing a feedforward pathogenic loop.12 There is evidence of PARP-1 activation in the substantia nigra, which may contribute to the pathogenesis of PD and constitute a therapeutic target for disease modification.10,13 This is potentially relevant as PARP-1 inhibitors are currently being used clinically as synergizing agents in the treatment of cancer.3,14 There are comprehensive reviews on the role of PARP-1 in disease.8-11,15 A brief review of the effects of PARP-1 functions may thus be relevant to neurologists (see the figure).