The mechanisms involved in neuronal loss in Parkinson's disease (PD) are not known, although recent studies performed in PD experimental models suggest that cdk5/p25 plays a predominant role. In the present study, we examined the gyrus cinguli of cases with PD and compared them with age-matched controls, and we demonstrated an activation of the calpain/cdk5 pathway. We found an increase in the p25/p35 immunoreactivity ratio and in the expression of transcription factor E2F-1. Our results implicate the cdk5/p25 pathway and re-entry into the cell cycle in the process of neuronal loss in patients with PD.