Abstract
Recent evidence suggests that the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) is involved in the pathology of Huntington's Disease (HD). While animals lacking PGC-1alpha express lower levels of genes involved in antioxidant defense and oxidative phosphorylation in the brain, little is known about other targets for PGC-1alpha in neuronal cells and whether there are ways to pharmacologically target PGC-1alpha in neurons. Here, PGC-1alpha overexpression in SH-SY5Y neuroblastoma cells upregulated expression of genes involved in mitochondrial function, glucose transport, fatty acid metabolism, and synaptic function. Overexpression also decreased vulnerability to hydrogen peroxide-induced cell death and caspase 3 activation. Treatment of cells with the histone deacetylase inhibitors (HDACi's) trichostatin A and valproic acid upregulated PGC-1alpha and glucose transporter 4 (GLUT4). These results suggest that PGC-1alpha regulates multiple pathways in neurons and that HDACi's may be good candidates to target PGC-1alpha and GLUT4 in HD and other neurological disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Apoptosis / genetics
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Biological Transport / genetics
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Caspase 3 / metabolism
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology
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Fatty Acids / metabolism
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Gene Expression Regulation*
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Glucose / metabolism
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Glucose Transporter Type 4 / genetics
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Heat-Shock Proteins / metabolism*
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Histone Deacetylase Inhibitors
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Histone Deacetylases / metabolism
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Humans
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Huntington Disease / enzymology
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Huntington Disease / genetics
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Huntington Disease / metabolism
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Hydrogen Peroxide / pharmacology
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Hydroxamic Acids / pharmacology
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Neuroblastoma
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Neurons / enzymology
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Neurons / metabolism*
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Transcription Factors / metabolism*
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Valproic Acid / pharmacology
Substances
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Enzyme Inhibitors
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Fatty Acids
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Glucose Transporter Type 4
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Heat-Shock Proteins
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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PPARGC1A protein, human
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Transcription Factors
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trichostatin A
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Valproic Acid
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Hydrogen Peroxide
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Caspase 3
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Histone Deacetylases
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Glucose