title: Neuroprotective effects of PPAR-γ 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-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.
authors: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Jing
authors: J
authors: Jin
authors: Jennifer
authors: J
authors: Albertz
authors: Zhihong
authors: Z
authors: Guo
authors: Qi
authors: Q
authors: Peng
authors: Gay
authors: G
authors: Rudow
authors: Juan C
authors: JC
authors: Troncoso
authors: Christopher A
authors: CA
authors: Ross
authors: Wenzhen
authors: W
authors: Duan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005971:Glutamates / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000068797:Orexins; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D037761:Sirtuins / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D019208:Brain-Derived Neurotrophic Factor; D005971:Glutamates; C000596229:HCRT protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D000068797:Orexins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D000077154:Rosiglitazone; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; C516592:SIRT6 protein, human; D037761:Sirtuins
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