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

Abstract

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator activated receptor γ co-activator protein-1 α (PGC-1α) in Parkinson’s disease (PD) and in animal or cellular models of PD. The role of PGC-1α 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-1α isoforms expressed in SH-SY5Y cells and these four isoforms are expressed across subregions of mouse brain. Adult conditional PGC-1α knockout 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-1α isoforms and mitochondria markers. Our findings suggest that all four isoforms of PGC-1α are required for proper expression of mitochondrial proteins in SNpc DA neurons and that PGC-1α is essential for SNpc DA neuronal survival possibly through maintenance of mitochondrial function.

Significance Statement: Recent studies indicate a role for PGC-1α in maintaining dopaminergic function as well as promoting survival against toxic environments when overexpressed. It is not yet known if PGC-1α is required for adult dopaminergic neuronal viability. To address this hypothesis we investigated dopaminergic neuronal viability in mice following adult conditional knockout of PGC-1α and find that loss of PGC-1α is sufficient to result in the loss of dopaminergic neurons.