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Neuroprotective effects of PPAR-? agonist rosiglitazone in N171-82Q mouse model of Huntington's disease.

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-?) is a transcriptional factor that plays a key role in regulating genes involved in energy metabolism; recent studies demonstrated that PPAR-? activation prevented mitochondrial depolarization in cells expressing mutant HTT and attenuated neurodegeneration in various models of neurodegenerative diseases. PPAR-?-coactivator 1? (PGC-1 ?) transcription activity is also impaired by mutant HTT. We now report that the PPAR-? 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-?. 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-1? reduction and increased Sirt6 protein levels in HD mouse brain. Our results suggest that modifying the PPAR-? pathway plays a beneficial role in rescuing motor function as well as glucose metabolic abnormalities in HD.

SUBMITTER: Jin J

PROVIDER: S-EPMC3642978 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease.

Jin Jing J Albertz Jennifer J Guo Zhihong Z Peng Qi Q Rudow Gay G Troncoso Juan C JC Ross Christopher A CA Duan Wenzhen W

Journal of neurochemistry 20130305 3

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 ...[more]

PMID: 23373812

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Project description:Our aim was to find an effective treatment for the dysfunction in energy regulation and hypothalamic integrity occurring in many HuntingtonM-bM-^@M-^Ys disease (HD) patients and mouse models. HD is a neurodegenerative disease caused by an expanded CAG repeat and is characterized by mutant huntingtin aggregates, cell death, progressive motor impairment, and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, sleep, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. Male B6C3-Tg(HD82Gln)81Dbo/J (N171-82Q) mice and age-matched wild-type (WT) mice were used. Transgenic mice were identified by PCR analysis of tail DNA. N171-82Q mice express 82 polyglutamine repeats and display multiple HuntingtonM-bM-^@M-^Ys disease-like symptoms. Either Ex-4 (n=10, 300 M-BM-5L of 0.1 M-BM-5mol/L solution, Bachem, Torrance, CA), the GLP-1-transferrin hybrid molecule (n=10, GLP-1Tf, 1mg/kg), insulin (n=10, 5Units, Lantus) or a saline vehicle treatment (n=10, phosphate buffered saline, PBS; Sigma, St. Louis, MO) was administered by a once-daily subcutaneous injection. Injections were started when animals were pre-symptomatic (2 months of age) and continued for 5 weeks. 3 Mice from each treatment qroup were used for the microarray analysis. RNA was extracted from frozen hypothalamus tissue using 1.0mm glass beads (BioSpec Products, Inc.) in a Precellys 24 Tissue Homogenizer (Bertin Technologies) and Qiagen RNeasy Mini Kits according to manufacturer's specifications. Quality and quantity of the total RNA was checked with the Agilent 2100 bioanalyzer using RNA 6000 Nano chips. The standard Illumina protocol using Illumina TotalPrep RNA Amplification Kit (Ambion; Austin, TX, cat # IL1791) was used to biotin label the aRNA generated and then hybridized to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips (Illumina, San Diego, CA). Arrays were scanned at a resolution of 0.8um using the Beadstation 500 X from Illumina.

Dataset Information

Neuroprotective effects of PPAR-? agonist rosiglitazone in N171-82Q mouse model of Huntington's disease.

Publications

Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease.

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