Resveratrol protects against peripheral deficits in a mouse model of Huntington's disease
Introduction
Sirtuins comprise a class of histone deacetylases that play a key role in modulating vital cellular functions, such as metabolism, gene transcription and senescence. The first sirtuin to be extensively studied was the yeast silent information regulator factor 2 (Sir2), a class III NAD+-dependent histone deacetylase (Gottlieb & Esposito, 1989, Shore et al., 1984, Kaeberlein et al., 1999). Studies have shown that a duplicate copy of the sir-2.1 gene (a Sir2 ortholog) in Caenorhabditis elegans and the Sir2 gene in Drosophila melanogaster induce life-extending effects (Rogina & Helfand, 2004, Anderson et al., 2003a, Anderson et al., 2003b, Lin et al., 2000). There are seven mammalian Sir2 homologs (SIRT1–SIRT7). Of the seven homologs, SIRT1 possesses the most similar biochemical activities to Sir2 in that it functions as an NAD+-dependent protein deacetylase (Outeiro et al., 2008).
The understanding of sirtuins' biological roles, more specifically that of SIRT1, has been greatly enhanced as a result of the discovery of resveratrol as an activator of SIRT1 (Outeiro et al., 2008). Resveratrol is a natural polyphenolic compound found predominantly in the skin of red grapes and in red wine. It increases SIRT1 activity, thus increasing the deacetylation of SIRT1's target proteins (Lagouge et al., 2006). A major substrate of SIRT1 that plays a principal role in modulating cell metabolic processes is PPARγ co-activator-1α (PGC-1α) (Lagouge et al., 2006, Baur et al., 2006, Rodgers et al., 2005). Lagouge et al. (2006) showed that resveratrol increased PGC-1α activity by enhancing SIRT1-mediated deacetylation of PGC-1α. Increasing PGC-1α activity leads to upregulated expression of the gene encoding the nuclear respiratory factor-1 (NRF-1) protein. NRF-1 activates the mitochondrial transcription factor (Tfam) and in turn resulting in increased mitochondrial DNA replication and transcription (Scarpulla, 2002). Additionally, increasing PGC-1α activity leads to greater expression of uncoupling protein-1 (UCP-1), a mitochondria-specific uncoupling protein (Puigserver et al., 1998). Lagouge et al. (2006) showed that enhancement of the PGC-1α signaling pathway resulted in increased mitochondrial biogenesis and function, as shown by increased oxidative capacity in skeletal muscle and better resistance to muscle fatigue. Further in vivo studies performed on mice fed a high-calorie diet showed that resveratrol increased PGC-1α activity, which improved metabolic function by increasing numbers of mitochondria (Baur et al., 2006). As a result, mice fed a high-calorie diet supplemented by resveratrol showed improved survival and motor function (Lagouge et al., 2006, Baur et al., 2006).
The positive effects of increased PGC-1α activity through enhanced SIRT1 activation may not only be beneficial in the context of a high-calorie diet but may also be important in mitigating the pathogenesis of neurodegenerative diseases (Rocha-Gonzalez et al., 2008, Okamoto et al., 2009). Resveratrol has been shown to prevent the toxic effects of the Parkinson's disease linked alpha-synuclein in a neuroblastoma cell line (Albani et al., 2009). In a mouse model of Alzheimer's disease (AD), administration of resveratrol resulted in diminished plaque formation (Karuppagounder et al., 2009), reduced neurodegeneration in the hippocampus and prevented learning impairment (Kim et al., 2007, Vingtdeux et al., 2008). These effects were accompanied by decreased PGC-1α acetylation (Kim et al., 2007). Resveratrol was also protective in a cell model of amyotrophic lateral sclerosis (ALS) (Kim et al., 2007). Furthermore, an SIRT1 lentviral injection in the hippocampus of a mouse model of AD resulted in a significant increase in neuronal survival (Kim et al., 2007). Resveratrol produced neuroprotective effects in a C. elegans model of polyglutamine cytotoxicity (Parker et al., 2005). Transgenic mice overexpressing SIRT1 displayed improved metabolic activity, including reduced blood cholesterol and blood glucose as well as improved motor performance (Bordone et al., 2007). The multiple lines of evidence demonstrating beneficial effects of increasing SIRT1 and PGC-1α activity in various neurodegenerative disease models suggest potential beneficial therapeutic effects of SIRT1 and PGC-1α upregulation in Huntington's disease (HD).
HD is an autosomal dominant neurodegenerative disorder characterized by progressive motor and cognitive impairment (Browne & Beal, 2004, Nance, 1997). It is caused by a polyglutamine repeat expansion in the huntingtin (htt) gene. Studies in transgenic mice and human microarrays showed that mitochondrial dysfunction, which accompanies HD neurodegeneration, may be due to defective PGC-1α activity (McGill & Beal, 2006, Weydt et al., 2006, Cui et al., 2006). Recent studies showed a genetic link of PGC-1α polymorphisms to age of onset of HD (Taherzadeh-Fard et al., 2009, Weydt et al., 2009). Overexpression of PGC-1α counteracted the deleterious effects of the mitochondrial complex II inhibitor, 3-nitropropionic acid (3-NP), in striatal HdhQ111 neuronal cells (Cui et al., 2006). Injection of a lentiviral vector expressing PGC-1α into the striatum of R6/2 HD transgenic mice attenuated striatal cell atrophy (Cui et al., 2006).
In light of the promising health benefits of resveratrol, as well as its potent ability to activate PGC-1α, we obtained a proprietary resveratrol preparation, SRT501-M, and investigated its effects on PGC-1α activity in the N171-82Q transgenic mouse model of HD. We found that SRT501-M increased PGC-1α mRNA levels and had protective effects in peripheral tissues, by reducing vacuolation in the brown adipose tissue and decreasing elevated blood glucose levels in N171-82Q transgenic mice. However, in the striatum, there was no increase in PGC-1α, NRF-1 or Tfam mRNA levels, consistent with the lack of improvement of motor performance, weight loss, striatal atrophy and survival in HD transgenic mice.
Section snippets
Animals
N171-82Q transgenic mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA). The colony was bred and maintained on a B6C3F1 background. Offspring were genotyped using a PCR assay on tail DNA. All mice were housed 4–5 per cage with free access to food and water for 24 hr, under standard conditions with a 12:12-h light/dark cycle. Wild-type and N171-82Q transgenic mice were assigned to their respective groups according to treatment with the resveratrol preparation, SRT501-M, or with a
SRT501-M administration reduced vacuolation and upregulated gene expression of PGC-1α and downstream targets in the brown adipose tissue of N171-82Q transgenic mice
N171-82Q transgenic mice are known to have metabolic defects, among which are defects in thermoregulation. In mice, the main tissue responsible for the body's response to temperature change is the brown adipose tissue. Therefore, brown adipose tissue vacuolation was analyzed in 120-day-old mice by both hematoxylin and eosin staining and oil red O staining in order to confirm the presence of neutral lipid vacuoles (Fig. 1A). In our analysis of four wild-type mice treated with the vehicle and six
Discussion
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide polyglutamine repeat expansion in the huntingtin (htt) protein (Bates, 1993, Bates, 2005). HD is characterized by personality changes, progressive cognitive decline, chorea and ultimately death (Nance, 1997). There is also a loss of medium spiny neurons of the striatum and impaired mitochondrial function and energy metabolism (Outeiro et al., 2008, Weydt et al., 2006, Grunewald & Beal, 1999).
Acknowledgments
We thank Sirtris Pharmaceuticals (Cambridge, MA, USA) for providing the SRT501-M and the vehicle. We also thank the Weill Cornell Medical College Microarray Core Facility for performing qRT-PCR. This work was supported by the National Institute of Health grant NS39258 and by the Huntington's Disease Society of America-Coalition for the Cure.
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