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

TLDR

PAR promotes α‑synuclein toxicity, yet how pathologic α‑synuclein drives neurodegeneration in Parkinson’s disease remains poorly understood. The authors used the α‑synuclein preformed fibril (α‑syn PFF) model of sporadic Parkinson’s disease to investigate this process. They showed that α‑syn PFF activates PARP‑1, generating PAR that converts α‑syn PFF into a 25‑fold more toxic strain (PAR‑α‑syn PFF); inhibition or knockout of PARP‑1 protects mice, and elevated PAR in cerebrospinal fluid and substantia nigra of PD patients implicates PARP activation in disease pathogenesis via parthanatos and toxic strain conversion. Kam et al., Science, this issue p.

Abstract

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