Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator-activated receptor gamma coactivator protein-1 alpha (PGC-1 alpha) in PD and in animal or cellular models of PD. The role of PGC-1 alpha in the function and survival of substantia nigra pars compacta (SNpc) dopamine neurons is not clear. Here we find that there are four different PGC-1 alpha isoforms expressed in SH-SY5Y cells, and these four isoforms are expressed across subregions of mouse brain. Adult conditional PGC-1 alpha knock-out mice show a significant loss of dopaminergic neurons that is accompanied by a reduction of dopamine in the striatum. In human PD postmortem tissue from the SNpc, there is a reduction of PGC-1 alpha isoforms and mitochondria markers. Our findings suggest that all four isoforms of PGC-1 alpha are required for the proper expression of mitochondrial proteins in SNpc DA neurons and that PGC-1 alpha is essential for SNpc DA neuronal survival, possibly through the maintenance of mitochondrial function.