Identification of novel targets for PGC-1alpha and histone deacetylase inhibitors in neuroblastoma cells.
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.
Cowell
Rita M
RM
Department of Psychiatry, University of Alabama, Birmingham, AL 35294, USA. rcowell@uab.edu
Talati
Pratik
P
Blake
Kathryn R
KR
Meador-Woodruff
James H
JH
Russell
James W
JW
D017209:Apoptosis / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C012589:trichostatin A; D014635:Valproic Acid; D006861:Hydrogen Peroxide; D053148:Caspase 3; D006655:Histone Deacetylases; D005947:Glucose