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Potential Role of Sirtuin As a Therapeutic Target for Neurodegenerative Diseases

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Potential Role of Sirtuin As a Therapeutic Target for Neurodegenerative Diseases REVIEW Print ISSN 1738-6586 / On-line ISSN 2005-5013 J Clin Neurol 2009 ;5:120-125 10.3988/jcn.2009.5.3.120 Potential Role of Sirtuin as a Therapeutic Target for Neurodegenerative Diseases Seol-Heui Han, MD, PhD Department of Neurology, Konkuk University Medical Center, Center for Geriatric Neuroscience Research, Institute of Biomedicalscience and Technology, Konkuk University, Seoul, Korea Received February 18, 2009 Revised August 18, 2009 The sirtuins (SIRTs) are protein-modifying enzymes that are distributed ubiquitously in all or- Accepted August 18, 2009 ganisms. SIRT1 is a mammalian homologue of yeast nicotinamide-adenine-dinucleotide-de- pendent deacetylase silent information regulator 2 (known as Sir2), which is the best-charac- Correspondence terized SIRT family member. It regulates longevity in several model organisms and is involved Seol-Heui Han, MD, PhD Department of Neurology, in several processes in mammalian cells including cell survival, differentiation, and metabo- Konkuk University Medical Center, lism. SIRT1 induction, either by SIRT-activating compounds such as resveratrol, or metabolic Center for Geriatric conditioning associated with caloric restriction, could have neuroprotective qualities and thus Neuroscience Research, delay the neurodegenerative process, thereby promoting longevity. However, the precise me- Institute of Biomedicalscience and chanistic liaison between the activation of SIRT and extended healthy aging or delaying age- Technology, Konkuk University, related diseases in humans has yet to be established. 4-12 Hwayang-dong, Gwangjin-gu, J Clin Neurol 2009;5:120-125 Seoul 143-729, Korea Tel +82-2-2030-7561 Key Wordsaasirtuins, therapeutic target, longevity, neurodegenerative diseases. Fax +82-2-2030-7469 E-mail [email protected] Introduction species, and rodents, and it has been proposed that the sir- tuins (SIRTs) might at least partly mediate this effect.2 Thus, Neurodegenerative disorders including Huntington’s disease, activating molecular pathways that slow the process of aging Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), may provide an outstanding strategy for treating and prevent- and Alzheimer’s disease (AD) are characterized by irreversi- ing these conditions. This is where SIRTs may come into play, bility, a progressive clinical course, and idiopathic degener- which are nicotinamide adenine dinucleotide (NAD+)-depen- ation of specific selectively vulnerable neuronal populations. dent enzymes that have emerged as important regulators of These debilitating neurodegenerative diseases are inherently diverse biological processes and are referred to as either SIRTs associated with the accumulation of misfolded proteins that or silent information regulator 2 (Sir2)-like proteins. They con- adversely affect neuronal connectivity and plasticity, and trig- stitute the class III histone deacetylases and are conserved ger cell-death-signaling pathways.1 However, the precise se- from bacteria to humans.3 The founding member, yeast Sir2 quence of the events that underlie disease progression remains (ySir2), is essential for maintaining silent chromatin through to be identified, and this largely explains the absence of me- the deacetylation of histones. Since the discovery of the invol- thods and effective therapeutic interventions for this group of vement of SIRT in apoptosis, cell survival, transcription, meta- diseases. While the misfolded proteins typically exhibit loss bolism, and aging, these activities have been implicated as dis- of function, mislocalization, and tendency toward aggrega- ease modifiers. This review highlights the role of SIRTs as po- tion, most of these processes are strongly influenced by aging, tential therapeutic targets for developing treatments for neuro- which is the predominant and unifying risk factor for neuro- degenerative disorders. Although SIRT1 and SIRT2 play im- degenerative diseases. portant roles in aging and neurodegeneration, very little is It is well established that low-calorie diets, known as “calo- known about their role in the central nervous system (CNS). ric restriction” (CR), extend lifespan in a wide variety of or- Therefore, following a brief description of the SIRTs in gen- ganisms including yeast, Caenorhabditis elegans, Drosophila eral, this review focuses on SIR1 and SIR2. 120 Copyright ⓒ 2009 Korean Neurological Association Han SH The Sirtuins as well as extrachromosomal rDNA circle formation.10 It is the best-investigated and most-well-understood member of the SIRTs, a family of NAD+-dependent deacetylases and/or ad- human family of SIRTs in terms of its endogenous function enosine diphosphate (ADP)-ribosyltransferases, are an evo- and activity, and is suggested to play an essential role in life- lutionarily conserved class of proteins that regulate various span extension (on CR), the oxidative stress response [poly cellular functions such as genome maintenance, longevity, (ADP-ribose) polyMerase], and regulation of forkhead trans- metabolism, and tolerance to oxidative stress.4-6 These enzy- cription factors (FOXOs) and p53. Other important subst- mes were first identified in yeast as silent information regu- rates of SIRT1 include, Ku70, peroxisome proliferator-acti- lators, hence the family name.7 SIRTs regulate cell functions vated receptor-γ coactivator-1α (PGC-1α), liver X receptor by deacetylating both histone and nonhistone targets. Sir2 in (LXR), and histones H1, H3, and H4, with histone deacety- Saccharomyces cerevisiae is the founding member of the lation causing gene silencing.11 SIRT1 physically interacts SIRT gene family, and its deacetylase activity is required for with p53 in the nucleus, an interaction that is enhanced after chromatin silencing at the mating-type loci, telomeres, and the induction of DNA damage. Acetylation of p53 results in the ribosomal DNA locus. Seven distinct Sir2 homologues the activation of p53 target genes such as p21, resulting in have been identified in humans (SIRT1-SIRT7), each having cell-cycle arrest, apoptosis, or senescence. Conversely, dea- distinct cellular targets and diverse cellular localizations. Ro- cetylation of p53 by SIRT1 decreases p53-mediated trans- bust protein deacetylase activity has been reported for SIRT1, criptional activation.12 SIRT1 activity results in the suppress- SIRT2, SIRT3, and SIRT5, whereas SIRT4, SIRT6, and SIRT7 ion of apoptosis induced by DNA damage or oxidative stress have no detectable enzymatic activity on a histone peptide (Fig. 1). substrate.8 The current consensus suggests that mammalian Since nuclear factor kappa-light-chain-enhancer of acti- SIRTs comprise two nuclear (SIRT1, SIRT6), one cytoplasmic vated B cells (NF-κB) exerts an antiapoptotic effect during (SIRT2), three mitochondrial (SIRT3, SIRT4, and SIRT5), tumor necrosis factor-α (TNF-α) activation, inhibition of NF- and one nucleolar (SIRT7) protein (Table 1).9 κB-mediated gene activation by SIRT1 sensitizes cells to ap- optosis during TNF-α treatment. Ku70 is a subunit of the Ku Sirtuin 1 protein complex, which is involved in the nonhomologous repair of DNA double-strand breaks. SIRT1 and Ku70 phy- SIRT1, which is found predominantly in the nucleus, has the sically interact in vivo, and overexpression of SIRT1 de- highest sequence homology to ySir2. An early insight into creases the acetylation level of Ku70, thereby promoting the one mechanism whereby Sir2 could increase the replicative antiapoptotic Bcl-2-associated X protein-Ku70 interaction. lifespan of yeast comes from the discovery that it acts at the Members of the FOXO family of transcription factors are nucleolus, inhibiting ribosomal DNA (rDNA) recombination involved in cellular processes that range from longevity, me- Table 1. Mammalian SIRTs: subcellular localization, putative targets, putative functions, and potential links with disease Subcellular Therapeutic SIRT Putative targets Putative function Potential link with diseases localization strategies SIRT1 Nucleus p53, Ku70, PPAR-γ, Activation Regulation of cell survival Aging, obesity, insulin PGC-1α, NF-κB, and metabolism, resistance, inflammation, p300, FOXO stress response control diabetes, heart failure, axonal degeneration, AIDS SIRT2 Cytoplasm/Nucleus α-tubulin, histone H4 Inhibition/ Regulation of microtubule Down-regulated in Activation? stability, heterochromatin human gliomas formation, cell-cycle regulation SIRT3 Mitochondria AceCS2, PGC-1α Activation Activation of mitochondrial Adaptive thermogenesis, function, regulation of overexpressed in node- thermogenesis positive breast cancer SIRT4 Mitochondria Glutamate Inhibition? Down-regulation of insulin Inhibits amino-acid- dehydrogenase secretion in response to stimulated insulin amino acids secretion SIRT5 Mitochondria Unknown Unknown Unknown Unknown SIRT6 Nucleus (associated DNA polymerase β Activation DNA repair/Control, ADP- Age-related diseases with heterochromatin) ribosyltransferase activity SIRT7 nucleus (concentrated RNA polymerase I Activation Regulation of rRNA synthesis Highly expressed in thyroid in nucleoli) and ribosome production cancers, overexpressed in node-positive breast cancer www.thejcn.com 121 Sirtuin for Neurodegenerative Diseases Resveratrol Cell Caloric Longevity survival restriction p53 pRB NF-κB FOXO Molecular LXR Growth SIRT 1 γ damage PPAR- arrest Histones NBS 1 Fig. 1. Convergence of stress signals on SIRT1, BCL 6 an upstream regulator of multiple effectors of the PGC 1-α stress response. SIRT: sirtuin, NF-κB: nuclear fac- Metabolic tor kappa-lightchain-enhancer
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