Program Project on the Pathogenesis and Treatment of Parkinson's Disease

摘要

This proposal represents the authors' continuing efforts to investigate the molecular mechanisms of Parkinson's disease (PD), a progressive neurodegenerative disorder that affects about 1 million people in the United States alone. Recent evidence suggests that inflammation plays a major role in the progressive nature of this disease. Thus, they are investigating the contributions of several pro-inflammatory enzymes that they found up-regulated in microglia following the use of 1-methyl-4-phenyl- 1,2,3,6-tetrahydropiridine (MPTP), the neurotoxin that is the cornerstone of PD research. They found that the number of substantia nigra pars compacta (SNpc) dopaminergic neurons (DA) in MPTP-treated IL-1 beta and IL-1R1 knockout mice did not differ from their nonknockout litter mates. This suggests that IL-1 beta and IL-1R1 may not be involved in the inflammatory response related to the necrotic form of neuronal death characteristic of the acute MPTP dosing schedule. However, they did note that cyclooxygenase-2 (COX-2) and cPLA2 are both up-regulated in SNpc DA neurons following acute MPTP. Because the acute MPTP dosing schedule is quite harsh, Core B characterized a subacute MPTP model of PD and found that this model exhibits at least 3 forms of neuronal death in the SNpc that are time- dependent: necrosis, apoptosis, and autophagy. This subacute model is closer to human PD in that it does not present an immediate end-stage situation characteristic of many neurotoxin-based PD models. The authors also have found in this subacute model that the number of SNpc DA neurons in MPTP-treated IL-1 beta and IL-1R1 knockout mice did not differ from their nonknockout litter mates during the inflammatory process, which is somewhat confusing. Thus, they are now using their neuronal/glial cultures and their neuronal- and glial- conditioned media to sort out the mechanisms involved in the initiation of the inflammatory response related to SNpc DA neuronal death.