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

PAR promotes α-synuclein toxicity How pathologic α-synuclein (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam et al. studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see the Perspective by Brundin and Wyse). They found that pathologic α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) and inhibition of PARP or knockout of PARP-1 protected mice from pathology. The generation of PAR by α-syn PFF–induced PARP-1 activation converted α-syn PFF to a strain that was 25-fold more toxic, termed PAR–α-syn PFF. An increase of PAR in the cerebrospinal fluid and evidence of PARP activation in the substantia nigra of PD patients indicates that PARP activation contributes to the pathogenesis of PD through parthanatos and conversion of α-syn to a more toxic strain. Science, this issue p. eaat8407; see also p. 521 Poly(ADP-ribose) polymerase-1 (PARP-1) accelerates the formation of pathological α-synuclein, resulting in cell death. INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Intracellular protein aggregates composed primarily of α-synuclein lead to neuronal dysfunction throughout the nervous system, ultimately accumulating in structures called Lewy bodies and neurites. Loss of substantia nigra pars compacta dopamine (DA) neurons and dystrophic striatal projections account for the major motor symptoms of PD, which include a rest tremor, slowness of movement, rigidity, and postural instability. Other neuronal systems are affected by pathologic α-synuclein and contribute to the nonmotor symptoms of PD, which include anxiety, depression, sleep disorders, autonomic dysfunction, constipation, and cognitive impairment. RATIONALE During the pathogenesis of PD, monomeric α-synuclein assembles into higher-ordered structures that ultimately become pathologic and drive neuronal cell death. Pathologic α-synuclein can spread from cell to cell, contributing to the progressive pathogenesis of PD. What drives the abnormal assembly of pathologic α-synuclein and the cell injury and death mechanisms that are activated by pathologic α-synuclein are not known. RESULTS Recombinant α-synuclein preformed fibrils (PFFs), which are similar in structure to those found in PD, were used to model pathologic α-synuclein both in vitro and in vivo. We investigated the cellular cell death pathways that contribute to and drive α-synuclein PFF–mediated neuronal cell death. Pathologic α-synuclein was found to activate nitric oxide synthase (NOS), causing DNA damage and poly(adenosine 5′-diphosphate–ribose) polymerase-1 (PARP-1) activation, leading to cell death via parthanatos. α-Synuclein PFF was found to primarily kill neurons via parthanatos, because necroptosis and autophagy inhibition had no effect on α-synuclein PFF neurotoxicity and there was only modest protection by caspase inhibition. Neuron-to-neuron transmission of pathologic α-synuclein and accompanying pathology and neurotoxicity in primary neuronal cultures were completely attenuated by clinically available PARP inhibitors or by deletion of PARP-1. α-Synuclein PFF–induced loss of DA neurons and biochemical and behavioral deficits in vivo were significantly prevented by PARP inhibition or lack of PARP-1. PAR generated by PARP-1 activation also binds to α-synuclein, accelerating its fibrillization and converting pathologic α-synuclein to a more misfolded compact strain with 25-fold enhanced toxicity. PAR-modified α-synuclein PFF–injected mice showed accelerated disease progression and phenotype compared to α-synuclein PFF–injected mice. Moreover, PAR levels were increased in the cerebrospinal fluid (CSF) in two independent patient cohorts and brains of PD patients, providing evidence that parthanatos may contribute to the pathogenesis of PD. CONCLUSION We identified PARP-1 activation and the generation of PAR as a key mediator of pathologic α-synuclein toxicity and transmission. Activation of parthanatos is the primary driver of pathologic α-synuclein neurodegeneration. Inhibition of PARP and depletion of PARP-1 substantially reduces the pathology induced by the transmission of pathologic α-synuclein. In a feed-forward loop, PAR converted pathologic α-synuclein to a more toxic strain and accelerated neurotoxicity both in vitro and in vivo. Consistent with the notion that PARP-1 activation plays a role in PD pathogenesis, PAR levels were increased in the CSF and brains of PD patients. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of DA neurons in PD and related α-synucleinopathies. Moreover, assessment of PAR levels in the CSF could serve as a theranostic biomarker for disease-modifying therapies in these disorders. PARP-1 is activated by α-synuclein PFF and PAR mediates cell death. Inhibition of PARP or deletion of PARP-1 reduces α-synuclein PFF–induced cell death. In a feed-forward loop, PAR causes the formation of a more toxic α-synuclein strain, resulting in accelerated pathologic α-synuclein transmission and toxicity. 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 are not known. Here, we found that pathologic α-syn activates poly(adenosine 5′-diphosphate–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 cerebrospinal fluid and brains of patients with PD, 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 neurons in PD.