| First Author | Ciron C | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 8 | Pages | 1861-76 |
| PubMed ID | 22246294 | Mgi Jnum | J:181883 |
| Mgi Id | MGI:5314311 | Doi | 10.1093/hmg/ddr618 |
| Citation | Ciron C, et al. (2012) Sustained expression of PGC-1alpha in the rat nigrostriatal system selectively impairs dopaminergic function. Hum Mol Genet 21(8):1861-76 |
| abstractText | Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1alpha induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC-1alpha progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1alpha induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1alpha prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1alpha is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1alpha overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by alpha-synuclein overexpression. Overall, we find that lasting overexpression of PGC-1alpha leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1alpha in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1alpha activity. |
