Neuroprotective effects of PPAR‐γ agonist rosiglitazone in N171‐82Q mouse model of Huntington's disease. (5th March 2013)

• Record Type: Journal Article
• Authors: Jin, Jing; Albertz, Jennifer; Guo, Zhihong; Peng, Qi; Rudow, Gay; Troncoso, Juan C.; Ross, Christopher A.; Duan, Wenzhen
• Is Part Of: Journal of neurochemistry. Volume 125:Number 3(2013:May)
• Page Start: 410
• Page End: 419
• Publication Date: 2013-03-05
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12190
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12190-abs-0001"> <title>Abstract</title> <p>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.</p> </abstract>