Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

Abstract

The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson’s disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD is not known. Here we found that pathologic α-syn activates poly (ADP-ribose) (PAR) polymerase-1 (PARP-1) and PAR generation accelerates the formation of pathologic α-syn resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebral spinal fluid and brains of PD patients suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease modifying therapy to prevent the loss of dopamine (DA) neurons in PD.

Challenges in Neuropharmacology

“…In particular, the discovery of pathologic accumulation and aggregation of αsyn as an underlying mechanism of Parkinson's disease raised certain attempts to degrade αsyn, as reported by Wrasidlo et al 7 Very recently, the molecular mechanisms by which pathologic αsyn causes neurodegeneration was elucidated. Kam et al 8 demonstrate that αsyn activates poly adenosine 5′-diphosphate-ribose (PAR) PARP-1. This enzyme itself then accelerates the formation of pathologic αsyn, resulting in cell death.…”

“…Very recently, the molecular mechanisms by which pathologic α‐syn causes neurodegeneration was elucidated. Kam et al . demonstrate that α‐syn activates poly adenosine 5′‐diphosphate‐ribose (PAR) PARP‐1.…”

Parkinson's disease: How do highly toxic α‐Synuclein/PAR aggregates mediate neuronal cell death?

“…To elucidate a pathological key mechanism of synucleinopathies, Kam and colleagues studied the interaction of α‐synuclein and its higher structures, that is, preformed fibrils (PFFs), with poly(ADP‐ribose) (PAR) and its polymerase 1 (PARP1) in several model systems and with in vitro studies. Activated PAR‐producing PARP1 induces a specific programmed cell death pathway called “parthanatos,” which is distinct from necrosis or apoptosis . To resolve whether PAR is a main actor in this network, the investigators monitored PAR levels in cerebrospinal fluid of PD patients in two independent cohorts.…”

“…Activated PAR-producing PARP1 induces a specific programmed cell death pathway called "parthanatos," which is distinct from necrosis or apoptosis. 1 To resolve whether PAR is a main actor in this network, the investigators monitored PAR levels in cerebrospinal fluid of PD patients in two independent cohorts. Cohort 1 contained 80 patients with a mean age of 66 years, a mean disease duration of 7.7 years, and 31 age-matched controls.…”

The Role of Poly(ADP‐ribose) in α‐Synuclein Neurodegeneration: Another Piece of the Puzzle for α‐Synucleinopathies

“…In a recent study, Kam et al describe a molecular cascade, explaining a way in which α‐synuclein (α‐syn) aggregates produce neurotoxicity both in vitro and in vivo. The authors investigated the role of PARP‐1 and PAR in α‐syn‐induced neurotoxicity.…”