Resveratrol protects against peripheral deficits in a mouse model of Huntington's disease.
Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription, cell survival and metabolism. Activation of SIRT1, a mammalian sirtuin, extends longevity and increases neuronal survival. An important substrate of SIRT1 is peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha), a principal regulator of energy metabolism, whose function is significantly impaired in Huntington's disease (HD). We studied the effects of a pharmacological preparation of the SIRT1 activator resveratrol (SRT501-M), in the N171-82Q transgenic mouse model of HD. We analyzed motor performance, survival, central and peripheral pathology and levels of PGC-1alpha expression. Administration of SRT501-M increased expression of PGC-1alpha, as well as its downstream targets, nuclear respiratory factor-1 (NRF-1) and uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT), but there was no effect on PGC-1alpha, NRF-1 or the mitochondrial transcription factor (Tfam) in the striatum. SRT501-M administration also reduced BAT vacuolation and decreased elevated blood glucose levels. However, there was no significant improvement in weight loss, motor performance, survival and striatal atrophy. Activation of the PGC-1alpha signaling pathway via resveratrol-induced activation of SIRT1, therefore, is an effective therapy in BAT, but not in the central nervous system of HD transgenic mice.
Ho
Daniel J
DJ
Weill Cornell Medical College, Department of Neurology and Neuroscience, 525 E. 68th Street, New York, NY 10065, USA.
Calingasan
Noel Y
NY
Wille
Elizabeth
E
Dumont
Magali
M
Beal
M Flint
MF
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use*; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D014157:Transcription Factors; D016896:Treatment Outcome
D000975:Antioxidants; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol