Therapeutic potential and challenges of targeting
sirtuins in neurodegenerative diseases

doi:10.1007/s11515-010-0700-7

Front. Biol.

2010, Vol. 5

Issue (4) : 324-330 https://doi.org/10.1007/s11515-010-0700-7

Research articles

Therapeutic potential and challenges of targeting sirtuins in neurodegenerative diseases

Li GAN,

Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco 94158, USA;

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Abstract Aging is the predominant risk factor for major neurodegenerative diseases. The underlying mechanisms are largely unknown. Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend lifespan when upregulated. Sirtuins are involved in fundamental mechanisms in age-related neurodegenerative diseases, including protein aggregation and homeostasis, survival and stress responses, and inflammatory processes. In this review, we will discuss the neurobiology of sirtuins and their multifaceted roles in the pathogenesis of neurodegenerative diseases. We will also examine the potential and challenges of targeting sirtuin pathways to treat these devastating conditions.

Keywords Sirtuins aging neurodegenerative disease

Issue Date: 01 August 2010

Cite this article:

Li GAN. Therapeutic potential and challenges of targeting sirtuins in neurodegenerative diseases[J]. Front. Biol., 2010, 5(4): 324-330.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-010-0700-7
https://academic.hep.com.cn/fib/EN/Y2010/V5/I4/324

	Adler A S, Kawahara T L, Segal E, Chang H Y (2008). Reversal of aging by NFkappaB blockade. Cell Cycle, 7(5): 556–559
	Adler A S, Sinha S, Kawahara T L, Zhang J Y, Segal E, Chang H Y (2007). Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev, 21(24): 3244–3257 doi: 10.1101/gad.1588507

	Berdichevsky A, Viswanathan M, Horvitz H R, Guarente L (2006). C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell, 125(6): 1165–1177
	Bordone L, Cohen D, Robinson A, Motta M C, van Veen E, Czopik A, Steele A D, Crowe H, Marmor S, Luo J, Gu W, Guarente L (2007). SIRT1 transgenic mice show phenotypes resembling calorierestriction. Aging Cell, 6(6): 759–767 doi: 10.1111/j.1474-9726.2007.00335.x
	Borra M T, Smith B C, Denu J M (2005). Mechanism of human SIRT1 activation by resveratrol. J Biol Chem, 280(17): 17187–17195 doi: 10.1074/jbc.M501250200
	Brunet A, Sweeney L B, Sturgill J F, Chua K F, Greer P L, Lin Y, Tran H, Ross S E, Mostoslavsky R, Cohen H Y, Hu L S, Cheng H L, Jedrychowski M P, Gygi S P, Sinclair D A, Alt F W, Greenberg M E (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303(5666): 2011–2015 doi: 10.1126/science.1094637
	Buck S W, Gallo C M, Smith J S (2004). Diversity in the Sir2 family of protein deacetylases. J Leukoc Biol, 75(6): 939–950 doi: 10.1189/jlb.0903424
	Cao S X, Dhahbi J M, Mote P L, Spindler S R (2001). Genomic profiling of short- and long-termcaloric restriction effects in the liver of aging mice. Proc Natl Acad Sci U S A, 98(19): 10630–10635 doi: 10.1073/pnas.191313598
	Chen D, Steele A D, Hutter G, Bruno J, Govindarajan A, Easlon E, Lin S J, Aguzzi A, Lindquist S, Guarente L (2008). The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration. Exp Gerontol, 43(12): 1086–1093 doi: 10.1016/j.exger.2008.08.050
	Chen D, Steele A D, Lindquist S, Guarente L (2005a). Increase in activity during calorie restriction requires Sirt1. Science, 310(5754): 1641 doi: 10.1126/science.1118357
	Chen J, Zhou Y, Mueller-Steiner S, Chen L F, Kwon H, Yi S, Mucke L, Gan L (2005b). SIRT1 protects againstmicroglia-dependent amyloid-beta toxicity through inhibiting NF-kappaBsignaling. J Biol Chem, 280(48): 40364–40374 doi: 10.1074/jbc.M509329200
	Cohen E, Bieschke J, Perciavalle R M, Kelly J W, Dillin A (2006). Opposing activities protect against age-onset proteotoxicity. Science, 313(5793): 1604–1610 doi: 10.1126/science.1124646
	Cohen E, Du D, Joyce D, Kapernick E A, Volovik Y, Kelly J W, Dillin A (2010). Temporal requirements of insulin/IGF-1 signaling forproteotoxicity protection. Aging Cell, 9(2): 126–134 doi: 10.1111/j.1474-9726.2009.00541.x
	Cohen H Y, Miller C, Bitterman K J, Wall N R, Hekking B, Kessler B, Howitz K T, Gorospe M, de Cabo R, Sinclair D A (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 305(5682): 390–392 doi: 10.1126/science.1099196
	Cui L, Jeong H, Borovecki F, Parkhurst C N, Tanese N, Krainc D (2006). Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell, 127(1): 59–69
	Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia M P, Invidia L, Celani L, Scurti M, Cevenini E, Castellani G C, Salvioli S (2007). Inflammaging and anti-inflammaging: a systemic perspectiveon aging and longevity emerged from studies in humans. Mech Ageing Dev, 128(1): 92–105 doi: 10.1016/j.mad.2006.11.016
	Frye R A (2000). Phylogenetic classification of prokaryoticand eukaryotic Sir2-like proteins. Biochem Biophys Res Commun, 273(2): 793–798 doi: 10.1006/bbrc.2000.3000
	Gan L, Mucke L (2008). Paths of convergence: sirtuins in aging and neurodegeneration. Neuron, 58(1): 10–14 doi: 10.1016/j.neuron.2008.03.015
	Gr?nroos E, Hellman U, Heldin C H, Ericsson J (2002). Control of Smad7 stability by competitionbetween acetylation and ubiquitination. Mol Cell, 10(3): 483–493 doi: 10.1016/S1097-2765(02)00639-1
	Hardy J, Selkoe D J (2002). The amyloid hypothesis of Alzheimer’s disease:progress and problems on the road to therapeutics. Science, 297(5580): 353–356 doi: 10.1126/science.1072994
	Hirschey M D, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard D B, Grueter C A, Harris C, Biddinger S, Ilkayeva O R, Stevens R D, Li Y, Saha A K, Ruderman N B, Bain J R, Newgard C B, Farese R V Jr, Alt F W, Kahn C R, Verdin E (2010). SIRT3 regulates mitochondrial fatty-acid oxidation byreversible enzyme deacetylation. Nature, 464(7285): 121–125 doi: 10.1038/nature08778
	Ito A, Kawaguchi Y, Lai C H, Kovacs J J, Higashimoto Y, Appella E, Yao T P (2002). MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J, 21(22): 6236–6245 doi: 10.1093/emboj/cdf616
	Jin Y H, Jeon E J, Li Q L, Lee Y H, Choi J K, Kim W J, Lee K Y, Bae S C (2004). Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibitsubiquitination-mediated degradation. J Biol Chem, 279(28): 29409–29417 doi: 10.1074/jbc.M313120200
	Joseph S B, Castrillo A, Laffitte B A, Mangelsdorf D J, Tontonoz P (2003). Reciprocal regulation of inflammation and lipid metabolismby liver X receptors. Nat Med, 9(2): 213–219 doi: 10.1038/nm820
	Kabe Y, Ando K, Hirao S, Yoshida M, Handa H (2005). Redox regulation of NF-kappaB activation: distinct redox regulation betweenthe cytoplasm and the nucleus. Antioxid Redox Signal, 7(3―4): 395–403 doi: 10.1089/ars.2005.7.395
	Kaeberlein M, Kirkland K T, Fields S, Kennedy B K (2004). Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol, 2(9): E296 doi: 10.1371/journal.pbio.0020296
	Kaeberlein M, McVey M, Guarente L (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by twodifferent mechanisms. Genes Dev, 13(19): 2570–2580 doi: 10.1101/gad.13.19.2570
	Kawahara T L, Michishita E, Adler A S, Damian M, Berber E, Lin M, McCord R A, Ongaigui K C, Boxer L D, Chang H Y, Chua K F (2009). SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependentgene expression and organismal life span. Cell, 136(1): 62–74
	Kenyon C (2001). A conserved regulatory system foraging. Cell, 105(2): 165–168
	Kim D, Nguyen M D, Dobbin M M, Fischer A, Sananbenesi F, Rodgers J T, Delalle I, Baur J A, Sui G, Armour S M, Puigserver P, Sinclair D A, Tsai L H (2007). SIRT1 deacetylase protects against neurodegeneration in models forAlzheimer’s disease and amyotrophic lateral sclerosis. EMBO J, 26(13): 3169–3179 doi: 10.1038/sj.emboj.7601758
	Kim S C, Sprung R, Chen Y, Xu Y, Ball H, Pei J, Cheng T, Kho Y, Xiao H, Xiao L, Grishin N V, White M, Yang X J, Zhao Y (2006). Substrate and functional diversityof lysine acetylation revealed by a proteomics survey. Mol Cell, 23(4): 607–618 doi: 10.1016/j.molcel.2006.06.026
	Klein W L (2002). Abeta toxicity in Alzheimer’sdisease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int, 41(5): 345–352 doi: 10.1016/S0197-0186(02)00050-5
	Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006). Resveratrol improves mitochondrial function and protects against metabolic diseaseby activating SIRT1 and PGC-1alpha. Cell, 127(6): 1109–1122
	Lee I H, Cao L, Mostoslavsky R, Lombard D B, Liu J, Bruns N E, Tsokos M, Alt F W, Finkel T (2008). A role for the NAD-dependent deacetylaseSirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A, 105(9): 3374–3379 doi: 10.1073/pnas.0712145105
	Lesné S, Koh M T, Kotilinek L, Kayed R, Glabe C G, Yang A, Gallagher M, Ashe K H (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440(7082): 352–357
	Levine B, Kroemer G (2008). Autophagy in the pathogenesis of disease. Cell, 132(1): 27–42
	Li X, Zhang S, Blander G, Tse J G, Krieger M, Guarente L (2007). SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell, 28(1): 91–106 doi: 10.1016/j.molcel.2007.07.032
	Li Y, Xu W, McBurney M W, Longo V D (2008). SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab, 8(1): 38–48 doi: 10.1016/j.cmet.2008.05.004
	Lin M T, Beal M F (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerativediseases. Nature, 443(7113): 787–795 doi: 10.1038/nature05292
	Lin S J, Defossez P A, Guarente L (2000). Requirement of NAD and SIR2 for life-span extension by calorie restriction inSaccharomyces cerevisiae. Science, 289(5487): 2126–2128 doi: 10.1126/science.289.5487.2126
	Lu T, Pan Y, Kao S Y, Li C, Kohane I, Chan J, Yankner B A (2004). Gene regulation and DNA damage in the ageing human brain. Nature, 429(6994): 883–891 doi: 10.1038/nature02661
	Luo J, Nikolaev A Y, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001). Negativecontrol of p53 by Sir2? promotes cell survival under stress. Cell, 107(2): 137–148
	Mattson M P, Meffert M K (2006). Roles for NF-kappaB in nerve cell survival, plasticity,and disease. Cell Death Differ, 13(5): 852–860 doi: 10.1038/sj.cdd.4401837

	Morley J F, Brignull H R, Weyers J J, Morimoto R I (2002). The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influencedby aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A, 99(16): 10417–10422 doi: 10.1073/pnas.152161099
	Pacholec M, Bleasdale J E, Chrunyk B, Cunningham D, Flynn D, Garofalo R S, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem, 285(11): 8340–8351 doi: 10.1074/jbc.M109.088682
	Parker J A, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C (2005). Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet, 37(4): 349–350 doi: 10.1038/ng1534
	Peck B, Chen C Y, Ho K K, Di Fruscia P, Myatt S S, Coombes R C, Fuchter M J, Hsiao C D, Lam E W (2010). SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther, 9(4): 844–855 doi: 10.1158/1535-7163.MCT-09-0971
	Pinkston-Gosse J, Kenyon C (2007). DAF-16/FOXO targets genes that regulate tumor growthin Caenorhabditis elegans. Nat Genet, 39(11): 1403–1409 doi: 10.1038/ng.2007.1
	Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers J T, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve A A, Pasinetti G M (2006). Neuronal SIRT1 activation as a novel mechanism underlyingthe prevention of Alzheimer disease amyloid neuropathology by calorierestriction. J Biol Chem, 281(31): 21745–21754 doi: 10.1074/jbc.M602909200
	Rass U, Ahel I, West S C (2007). Defective DNA repair and neurodegenerative disease. Cell, 130(6): 991–1004
	Rodgers J T, Lerin C, Haas W, Gygi S P, Spiegelman B M, Puigserver P (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 434(7029): 113–118 doi: 10.1038/nature03354
	Rogina B, Helfand S L (2004). Sir2 mediates longevity in the fly through a pathwayrelated to calorie restriction. Proc Natl Acad Sci U S A, 101(45): 15998–16003 doi: 10.1073/pnas.0404184101
	Saunders L R, Verdin E (2007). Sirtuins: critical regulators at the crossroads betweencancer and aging. Oncogene, 26(37): 5489–5504 doi: 10.1038/sj.onc.1210616
	Solomon J M, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano P S, Huber L J (2006). Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival followingDNA damage. Mol Cell Biol, 26(1): 28–38
	Sun Y, Yao J, Kim T W, Tall A R (2003). Expression of liver X receptor target genes decreasescellular amyloid beta peptide secretion. J Biol Chem, 278(30): 27688–27694 doi: 10.1074/jbc.M300760200
	Tanner K G, Landry J, Sternglanz R, Denu J M (2000). Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a uniqueproduct, 1-O-acetyl-ADP-ribose. Proc Natl Acad Sci U S A, 97(26): 14178–14182 doi: 10.1073/pnas.250422697
	Tanzi R E, Bertram L (2005). Twenty years of the Alzheimer’s disease amyloidhypothesis: a genetic perspective. Cell, 120(4): 545–555
	Tissenbaum H A, Guarente L (2001). Increased dosage of a sir-2 gene extends lifespan inCaenorhabditis elegans. Nature, 410(6825): 227–230 doi: 10.1038/35065638
	Vaziri H, Dessain S K, Ng Eaton E, Imai S I, Frye R A, Pandita T K, Guarente L, Weinberg R A (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell, 107(2): 149–159
	Wood J G, Rogina B, Lavu S, Howitz K, Helfand S L, Tatar M, Sinclair D (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430(7000): 686–689 doi: 10.1038/nature02789
	Yeung F, Hoberg J E, Ramsey C S, Keller M D, Jones D R, Frye R A, Mayo M W (2004). Modulation of NF-kappaB-dependent transcription andcell survival by the SIRT1 deacetylase. EMBO J, 23(12): 2369–2380 doi: 10.1038/sj.emboj.7600244
	Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan E G, Landreth G E, Vinters H V, Tontonoz P (2007). Attenuation of neuroinflammation and Alzheimer’sdisease pathology by liver x receptors. Proc Natl Acad SciU S A, 104(25): 10601–10606 doi: 10.1073/pnas.0701096104

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