COX-2 generated PGE2 - the culprit in the pathogenesis of Parkinson's disease? (360G-Wellcome-080782_Z_06_Z)

Neurodegenerative diseases pose one of the largest challenges in both the clinical and the research setting. My group has investigated the fundamental mechanisms underpinning cell death in Parkinson's disease (PD), which originates from the loss of dopaminergic neurons. We have demonstrated that cyclooxygenase (COX)-2 expression is increased in dopaminergic neurons in the substantia nigra pars compacta of PD patients (Teismann et al., PNAS 2003). In our Parkinson's disease model, mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), equivalent observations were made. COX-2 is instrumental in MPTP-induced neurotoxicity but our data suggest that the mechanism is not mediated by inflammatory cells (microglia/astrocytes). Our data are consistent with a major role for prostaglandin (PG) E2. Thus, COX-2 activity is paralleled by an increased expression of PGE2 in dopaminergic neurones. PGE2 can induce cytokine release and deprive the cell of oxygen, thus leading to cell death. In the proposed project we will investigate the function and mechanisms of PGE2 in the