Abstract
Huntington's disease (HD) is a devastating genetic neurodegenerative disease caused by CAG trinucleotide expansion in the exon-1 region of the huntingtin gene. Currently, no cure is available. It is becoming increasingly apparent that mutant Huntingtin (HTT) impairs metabolic homeostasis and causes transcriptional dysregulation. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcriptional factor that plays a key role in regulating genes involved in energy metabolism; recent studies demonstrated that PPAR-γ activation prevented mitochondrial depolarization in cells expressing mutant HTT and attenuated neurodegeneration in various models of neurodegenerative diseases. PPAR-γ-coactivator 1α (PGC-1 α) transcription activity is also impaired by mutant HTT. We now report that the PPAR-γ agonist, rosiglitazone (RSG), significantly attenuated mutant HTT-induced toxicity in striatal cells and that the protective effect of RSG is mediated by activation of PPAR-γ. Moreover, chronic administration of RSG (10 mg/kg/day, i.p) significantly improved motor function and attenuated hyperglycemia in N171-82Q HD mice. RSG administration rescued brain derived neurotrophic factor(BDNF) deficiency in the cerebral cortex, and prevented loss of orexin-A-immunopositive neurons in the hypothalamus of N171-82Q HD mice. RSG also prevented PGC-1α reduction and increased Sirt6 protein levels in HD mouse brain. Our results suggest that modifying the PPAR-γ pathway plays a beneficial role in rescuing motor function as well as glucose metabolic abnormalities in HD. Huntington's disease (HD) is a devastating neurodegenerative disease that no cure is available. We found that PPARγ agonist rosiglitazone normalizes the levels of the Sirt6, restores the levels of BDNF and PGC-1α in HD models. The protective effects of rosiglitazone in HD mice suggest that targeting the PPAR-γ signaling pathway should be considered in developing HD therapy.
Original language | English (US) |
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Pages (from-to) | 410-419 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 125 |
Issue number | 3 |
DOIs | |
State | Published - May 2013 |
Keywords
- BDNF
- PGC-1α
- PPAR-γ
- Sirt6
- glucose metabolism
- huntingtin
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience