EMBO J 2007 (Jul 11); 26 (13): 3169–3179 ~ FULL TEXT
Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT,
Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH
Howard Hughes Medical Institute,
Picower Insitute for Learning and Memory,
Riken-MIT Neuroscience Research Center,
Department of Brain and Cognitive Sciences,
Massachusetts Institute of Technology,
Boston, MA, USA
A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.
From the FULL TEXT Article:
Although neurodegenerative disorders are relatively cell type specific, many of the underlying pathogenic processes are similar, including protein misfolding, oxidative stress, cytoskeletal abnormalities, disruption of calcium homeostasis, and inflammation, all of which increase during aging (Bossy-Wetzel et al, 2004; Forman et al, 2004; Selkoe, 2004). The existence of related mechanisms underlying neurodegeneration raises the possibility of developing a class of therapeutic interventions that treat a variety of neurological disorders by activating the body's own defenses against age-related deterioration and cell death (Bossy-Wetzel et al, 2004; Forman et al, 2004; Selkoe, 2004). Studies from yeast identified the evolutionarily conserved NAD+-dependent deacetylase Sir2 as a critical regulator of the aging process (Kaeberlein et al, 1999; Imai et al, 2000; Anderson et al, 2003a, 2003b; Howitz et al, 2003; Cohen et al, 2004b).
An additional copy of the SIR2 gene extends lifespan in yeast and metazoans by a process seemingly analogous to caloric restriction (Lin et al, 2000; Anderson et al, 2003a, 2003b), a diet that delays diseases of aging in mammals including neurodegeneration (Luo et al, 2001; Vaziri et al, 2001; Langley et al, 2002; Howitz et al, 2003; Brunet et al, 2004; Cohen et al, 2004a, 2004b; Motta et al, 2004; Qin et al, 2006). Mammals possess seven Sir2 homologues (SIRT1-7) whose biological functions remain poorly defined. The SIRT1 gene is believed to provide cell protection during times of cell stress (Brunet et al, 2004; Cohen et al, 2004a, 2004b; Chen et al, 2005; Tang, 2006).
Consistent with this, knockdown of the SIRT1 gene in cultured mouse dorsal roots ganglion sensory neurons abrogates the protective effects of increased NAD+ synthesis on axonal degeneration following acute axotomy (Araki et al, 2004). On the other hand, a recent study suggests that SIRT1 is not required for NAD-dependent protection, rendering the role of SIRT1 in peripheral axotomy unclear (Wang et al, 2005). Furthermore, Sir2 seems to block extreme lifespan in post-mitotic cells in yeast, raising the possibility that SIRT1 may play a dual role in the CNS (Fabrizio et al, 2005). Most importantly, the role of SIRT1 in vivo in age-dependent chronic neurodegenerative disorders remains undefined.
From the FULL TEXT Article:
Collectively, our results demonstrate that it is possible to slow in vitro cell death as well as in vivo neurodegeneration and cognitive decline with resveratrol, a SIRT1-activating molecule, and by expression of SIRT1. We also provide evidence that the neuroprotective effect is due, at least in part, to deacetylation of K382-p53 (Figure 5). We do not rule out the possibility that other known substrates of SIRT1 are involved, such as Ku70, a protein that sequesters the apoptotic protein Bax from mitochondria (Brunet et al, 2004; Cohen et al, 2004a). Resveratrol may also stimulate the deacetylation of FOXO3/4 transcription factors, thereby enhancing gene expression of antioxidative molecules and upregulating DNA repair (Nguyen et al, 2002; Brunet et al, 2004; Smith et al, 2004). Another interesting candidate target for SIRT1 deacetylation activity is PGC-1alpha, which we have shown for the first time to be deacetylated in a model for neurodegeneration (p25 Tg) and in the brain, in response to resveratrol treatment. PGC-alpha activity was recently shown to play an important role in neuronal metabolism and detoxification of reactive oxygen species (St-Pierre et al, 2006), and our finding suggests that deacetylation and activation PGC-1alpha by enhanced SIRT1 activity may also be involved in the neuroprotection observed in our experiments. On the other hand, while our study and previous reports suggest that the activation of SIRT1 constitutes an important aspect of resveratrol action, we cannot rule out that resveratrol may interact with other biomolecules, besides SIRT1, to exert its neuroprotective effects.
SIRT1 is thought to be a key regulator of an evolutionarily conserved pathway that allows organisms to cope with adversity. Consistent with this notion, yeast Sir2 and mammalian SIRT1 are upregulated by various biological stresses, including caloric restriction, which has been shown to prevent numerous diseases of aging in mammals such as Alzheimer's disease (AD) (Lamming et al, 2004; Bordone and Guarente, 2005; Lombard et al, 2005). Of note, a reduction of ?-amyloid peptide, a hallmark of AD, occurs in brain of calorie-restricted animals and can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity (Marambaud et al, 2005; Tang, 2005; Qin et al, 2006). In this study, we show for the first time the ability of SIRT1 and SIRT1-activating molecules to prevent an age-dependent neurodegenerative disease caused by the toxic Cdk5 coactivator, p25, which has been implicated in various neurotoxic conditions such as AD, ALS and stroke. The induction of SIRT1 expression levels in various neurotoxic conditions may be interpreted as a neuroprotective adaptation response, implying role for SIRT1 as an important stress sensor molecule that links aging to neurodegeneration. Future research efforts will investigate the underlying mechanism for SIRT1 induction by neurotoxic stresses. Microarray analyses of p25 transgenic mice indicated elevated mRNA levels of SIRT1 (not shown), suggesting a transcriptional component for SIRT1 induction. On the other hand, rapid induction of SIRT1 in cultured neurons (Figure 1F) implies that post-translational mechanisms may also be involved.
Our results predict that positive intervention into SIRT1 activity, such as through intake of SIRT1-activating molecules, may have profound therapeutic benefits against various age-dependent neurodegenerative diseases. Conversely, it may be worthwhile to explore whether mechanisms that decrease SIRT1 activity or levels result in enhanced susceptibility to age-dependent neurodegeneration. While knockdown of SIRT1 did not appear to result in increased susceptibility to acute neurotoxic stimuli in cultured neurons (Supplementary Figure 5), the long-term effects of decreased SIRT1 levels per se or in chronic neurodegenerative conditions is an important question for future studies. Interestingly, the SIRT1 gene resides in a locus on chromosome 10 that is associated with familial AD (WIPO, international publication WO 2005/004815 A2) and future studies are planned to determine whether mutations or polymorphisms in SIRT1 affect the susceptibility of individuals to AD pathology.