Proliferating Cell Nuclear Antigen Binds DNA Polymerase-β and Mediates 1-Methyl-4-Phenylpyridinium-Induced Neuronal Death

The mechanisms leading to dopaminergic neuronal loss in the substantia nigra of patients with Parkinson disease (PD) remain poorly understood. We recently reported that aberrant DNA replication mediated by DNA polymerase-beta (DNA pol-beta) plays a causal role in the death of postmitotic neurons in an in vitro model of PD. In the present study, we show that both proliferating cell nuclear antigen (PCNA) and DNA pol-beta are required for MPP+-induced neuronal death. PCNA binds to the catalytic domain of DNA pol-beta in MPP+-treated neurons and in post-mortem brain tissues of PD patients. The PCNA-DNA pol-beta complex is loaded into DNA replication forks and mediates DNA replication in postmitotic neurons. The aberrant DNA replication mediated by the PCNA-DNA pol-beta complex induces p53-dependent neuronal cell death. Our results indicate that the interaction of PCNA and DNA pol-beta contributes to neuronal death in PD.