Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function

Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinsons 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-1), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1 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-1 progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1 induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1 prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1 is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1 overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by -synuclein overexpression. Overall, we find that lasting overexpression of PGC-1 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-1 in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1 activity.

Published in:
Human Molecular Genetics
Oxford University Press

 Record created 2012-01-19, last modified 2018-01-28

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