There is substantial evidence that impairment of peroxisome proliferator-activated receptor (PPAR)-γ-coactivator 1α (PGC-1α) levels and activity play an important role in Huntington's disease (HD) pathogenesis. We tested whether pharmacologic treatment with the pan-PPAR agonist bezafibrate would correct a deficiency of PGC-1α and exert beneficial effects in a transgenic mouse model of HD. We found that administration of bezafibrate in the diet restored levels of PGC-1α, PPARs and downstream genes to levels which occur in wild-type mice. There were significant improvements in phenotype and survival. In the striatum, astrogliosis and neuronal atrophy were attenuated and numbers of mitochondria were increased. Bezafibrate treatment prevented conversion of type I oxidative to type II glycolytic muscle fibers and increased the numbers of muscle mitochondria. Finally, bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice. These findings provide strong evidence that treatment with bezafibrate exerts neuroprotective effects which may be beneficial in the treatment of HD.
The constant high energy demand of neurons makes them rely heavily on their mitochondria. Dysfunction of mitochondrial energy metabolism leads to reduced ATP production, impaired calcium buffering, and generation of reactive oxygen species. There is strong evidence that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Huntington’s disease (HD). Studies over the past few years have implicated an impaired function of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), a transcriptional master co-regulator of mitochondrial biogenesis, metabolism and antioxidant defenses, in causing mitochondrial dysfunction in HD. Here we have attempted to discuss in a nutshell, the key findings on the role of PGC-1α in mitochondrial dysfunction in HD and its potential as a therapeutic target to cure HD.
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