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.
© 2013 International Society for Neurochemistry.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / metabolism
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Anilides / pharmacology
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Animals
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Brain / drug effects
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Brain / enzymology
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Brain / pathology
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Brain-Derived Neurotrophic Factor / metabolism
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Cell Line
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Disease Models, Animal
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glutamates / genetics
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Humans
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Huntingtin Protein
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Huntington Disease / complications
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Huntington Disease / drug therapy*
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Huntington Disease / genetics
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Huntington Disease / pathology
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Hyperglycemia / drug therapy
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Hyperglycemia / etiology
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Intracellular Signaling Peptides and Proteins / metabolism
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L-Lactate Dehydrogenase / metabolism
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Male
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Mice
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Mice, Transgenic
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Movement Disorders / drug therapy
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Movement Disorders / etiology
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Nerve Tissue Proteins / genetics
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Neurons / drug effects*
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Neurons / metabolism
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Neuropeptides / metabolism
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use*
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Orexins
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PPAR gamma / antagonists & inhibitors
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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RNA, Messenger / metabolism
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Rosiglitazone
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Sirtuins / metabolism
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Thiazolidinediones / pharmacology
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Thiazolidinediones / therapeutic use*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors
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Transfection
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Trinucleotide Repeat Expansion / genetics
Substances
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2-chloro-5-nitrobenzanilide
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Anilides
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Brain-Derived Neurotrophic Factor
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Glutamates
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HCRT protein, human
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HTT protein, human
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Huntingtin Protein
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Intracellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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Neuropeptides
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Neuroprotective Agents
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Orexins
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PPAR gamma
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA, Messenger
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Thiazolidinediones
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Trans-Activators
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Transcription Factors
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Rosiglitazone
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Adenosine Triphosphate
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L-Lactate Dehydrogenase
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SIRT6 protein, human
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Sirtuins