Sirtuin3 in Neurological Disorders | Bentham Science
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Current Drug Research Reviews

Editor-in-Chief

ISSN (Print): 2589-9775
ISSN (Online): 2589-9783

Review Article

Sirtuin3 in Neurological Disorders

Author(s): Farhath Sherin, S. Gomathy* and Shanish Antony

Volume 13, Issue 2, 2021

Published on: 07 December, 2020

Page: [140 - 147] Pages: 8

DOI: 10.2174/2589977512666201207200626

Price: $65

Open Access Journals Promotions 2
Abstract

Sirtuins are NAD+ dependent enzymes that have a predominant role in neurodegenerative disorders and also regulate the inflammatory process, protein aggregation, etc. The relationships between sirtuins with that of the nervous system and neurodegeneration, are widely studied. Sirtuins have a strong role in metabolic syndrome in mitochondria also. The activities of sirtuins can be altered by using small molecules that would be developed into drugs and it is proven that the manipulation of SIRT1 activity influences neurodegenerative disease models. They are interesting since using small molecules, which would be developed into a drug, it is feasible to alter the activities of sirtuins. Different functions of sirtuins depend upon their subcellular localization. In this review paper, we discuss different sirtuins, differential expression of sirtuins, and expression of sirtuin in the brain and briefly explains Sirtuin3 (SIRT3).

Keywords: Sirtuins, SIRT3, mitochondria, Parkinson’s disease, Alzheimer's disease, Huntington's disease.

Graphical Abstract
[1]
Herskovits AZ, Guarente L. Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res 2013; 23(6): 746-58.
[http://dx.doi.org/10.1038/cr.2013.70] [PMID: 23689277]
[2]
Min SW, Sohn PD, Cho SH, Swanson RA, Gan L. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci 2013; 5(5): 53.
[http://dx.doi.org/10.3389/fnagi.2013.00053] [PMID: 24093018]
[3]
Yalcin G. Sirtuins and neurodegeneration. J Neurol Neuromedicine 2018; 3(1): 13-20.
[http://dx.doi.org/10.29245/2572.942X/2017/1.1168]
[4]
Donmez G. The neurobiology of sirtuins and their role in neurodegeneration. Trends Pharmacol Sci 2012; 33(9): 494-501.
[http://dx.doi.org/10.1016/j.tips.2012.05.007] [PMID: 22749331]
[5]
Han SH. Potential role of sirtuin as a therapeutic target for neurodegenerative diseases. J Clin Neurol 2009; 5(3): 120-5.
[http://dx.doi.org/10.3988/jcn.2009.5.3.120] [PMID: 19826562]
[6]
Bause AS, Haigis MC. SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol 2013; 48(7): 634-9.
[http://dx.doi.org/10.1016/j.exger.2012.08.007] [PMID: 22964489]
[7]
Fifel K. Sirtuin 3: a molecular pathway linking sleep deprivation to neurological diseases. J Neurosci 2014; 34(28): 9179-81.
[http://dx.doi.org/10.1523/JNEUROSCI.1848-14.2014] [PMID: 25009250]
[8]
Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 2005; 280(14): 13560-7.
[http://dx.doi.org/10.1074/jbc.M414670200] [PMID: 15653680]
[9]
Weir HJ, Lane JD, Balthasar N. SIRT3: a central regulator of mitochondrial adaptation in health and disease. Genes Cancer 2013; 4(3-4): 118-24.
[http://dx.doi.org/10.1177/1947601913476949] [PMID: 24020003]
[10]
Shih J, Donmez G. Mitochondrial sirtuins as therapeutic targets for age-related disorders. Genes Cancer 2013; 4(3-4): 91-6.
[http://dx.doi.org/10.1177/1947601912474931] [PMID: 24019999]
[11]
Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 2016; 17(11): 679-90.
[http://dx.doi.org/10.1038/nrm.2016.93] [PMID: 27552971]
[12]
Anamika KA, Acharjee P, Acharjee A, Trigun SK. Mitochondrial SIRT3 and neurodegenerative brain disorders. J Chem Neuroanat 2019; 95: 43-53.
[http://dx.doi.org/10.1016/j.jchemneu.2017.11.009] [PMID: 29129747]
[13]
Rine J, Herskowitz I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 1987; 116(1): 9-22.
[PMID: 3297920]
[14]
Kincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci 2013; 5(5): 48.
[http://dx.doi.org/10.3389/fnagi.2013.00048] [PMID: 24046746]
[15]
Outeiro TF, Marques O, Kazantsev A. Therapeutic role of sirtuins in neurodegenerative disease. Biochim Biophys Acta 2008; 1782(6): 363-9.
[http://dx.doi.org/10.1016/j.bbadis.2008.02.010] [PMID: 18373985]
[16]
Imai S, Guarente L. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 2010; 31(5): 212-20.
[http://dx.doi.org/10.1016/j.tips.2010.02.003] [PMID: 20226541]
[17]
Du J, Zhou Y, Su X, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011; 334(6057): 806-9.
[http://dx.doi.org/10.1126/science.1207861] [PMID: 22076378]
[18]
Szegő ÉM, Outeiro TF, Kazantsev AG. Sirtuins in brain and neurodegenerative disease. In: Guarente L, Mostoslavsky R, Kazantsev A, Eds. Introductory review on sirtuins in biology aging and disease 2018; 175-95.
[19]
Osborne B, Bentley NL, Montgomery MK, Turner N. The role of mitochondrial sirtuins in health and disease. Free Radic Biol Med 2016; 100(1): 164-74.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.197] [PMID: 27164052]
[20]
Hallows WC, Albaugh BN, Denu JM. Where in the cell is SIRT3?- functional localization of an NAD+-dependent protein deacetylase. Biochem J 2008; 411(2): e11-3.
[http://dx.doi.org/10.1042/BJ20080336] [PMID: 18363549]
[21]
Lombard DB, Alt FW, Cheng HL, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 2007; 27(24): 8807-14.
[http://dx.doi.org/10.1128/MCB.01636-07] [PMID: 17923681]
[22]
Nakamura Y, Ogura M, Tanaka D, Inagaki N. Localization of mouse mitochondrial SIRT proteins: shift of SIRT3 to nucleus by co-expression with SIRT5. Biochem Biophys Res Commun 2008; 366(1): 174-9.
[http://dx.doi.org/10.1016/j.bbrc.2007.11.122] [PMID: 18054327]
[23]
Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 2010; 35(12): 669-75.
[http://dx.doi.org/10.1016/j.tibs.2010.07.003] [PMID: 20863707]
[24]
Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010; 12(6): 662-7.
[http://dx.doi.org/10.1016/j.cmet.2010.11.015] [PMID: 21109198]
[25]
Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol 2002; 158(4): 647-57.
[http://dx.doi.org/10.1083/jcb.200205057] [PMID: 12186850]
[26]
Bell EL, Guarente L. The SirT3 divining rod points to oxidative stress. Mol Cell 2011; 42(5): 561-8.
[http://dx.doi.org/10.1016/j.molcel.2011.05.008] [PMID: 21658599]
[27]
Silberman DM. Metabolism, neurodegeneration and epigenetics: Emerging role of Sirtuins. Neural Regen Res 2018; 13(3): 417-8.
[http://dx.doi.org/10.4103/1673-5374.228719] [PMID: 29623921]
[28]
Braidy N, Poljak A, Grant R, et al. Differential expression of sirtuins in the aging rat brain. Front Cell Neurosci 2015; 8(9): 1-16.
[http://dx.doi.org/10.3389/fncel.2015.00167]
[29]
Sidorova-Darmos E, Wither RG, Shulyakova N, et al. Differential expression of sirtuin family members in the developing, adult, and aged rat brain. Front Aging Neurosci 2014; 6(6): 333.
[http://dx.doi.org/10.3389/fnagi.2014.00333] [PMID: 25566066]
[30]
Sidorova-Darmos E, Sommer R, Eubanks JH. The role of SIRT3 in the brain under physiological and pathological conditions. Front Cell Neurosci 2018; 12(2): 196.
[http://dx.doi.org/10.3389/fncel.2018.00196] [PMID: 30090057]
[31]
Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci USA 2002; 99(21): 13653-8.
[http://dx.doi.org/10.1073/pnas.222538099] [PMID: 12374852]
[32]
Cooper HM, Spelbrink JN. The human SIRT3 protein deacetylase is exclusively mitochondrial. Biochem J 2008; 411(2): 279-85.
[http://dx.doi.org/10.1042/BJ20071624] [PMID: 18215119]
[33]
Fu J, Jin J, Cichewicz RH, et al. trans-(-)-ε-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease. J Biol Chem 2012; 287(29): 24460-72.
[http://dx.doi.org/10.1074/jbc.M112.382226] [PMID: 22648412]
[34]
Cheng A, Yang Y, Zhou Y, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab 2016; 23(1): 128-42.
[http://dx.doi.org/10.1016/j.cmet.2015.10.013] [PMID: 26698917]
[35]
Brandauer J, Andersen MA, Kellezi H, et al. AMP-activated protein kinase controls exercise training- and AICAR-induced increases in SIRT3 and MnSOD. Front Physiol 2015; 6(6): 85.
[http://dx.doi.org/10.3389/fphys.2015.00085] [PMID: 25852572]
[36]
Jiang DQ, Wang Y, Li MX, Ma YJ, Wang Y. SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway. Front Cell Neurosci 2017; 11(7): 7.
[http://dx.doi.org/10.3389/fncel.2017.00007] [PMID: 28197079]
[37]
Liu L, Peritore C, Ginsberg J, Kayhan M, Donmez G. SIRT3 attenuates MPTP-induced nigrostriatal degeneration via enhancing mitochondrial antioxidant capacity. Neurochem Res 2015; 40(3): 600-8.
[http://dx.doi.org/10.1007/s11064-014-1507-8] [PMID: 25555707]
[38]
Brown K, Xie S, Qiu X, et al. SIRT3 reverses aging-associated degeneration. Cell Rep 2013; 3(2): 319-27.
[http://dx.doi.org/10.1016/j.celrep.2013.01.005] [PMID: 23375372]
[39]
Kong X, Wang R, Xue Y, et al. Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 2010; 5(7): e11707.
[http://dx.doi.org/10.1371/journal.pone.0011707] [PMID: 20661474]
[40]
Kim SH, Lu HF, Alano CC. Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture. PLoS One 2011; 6(3): e14731.
[http://dx.doi.org/10.1371/journal.pone.0014731] [PMID: 21390294]
[41]
Villalba JM, Alcaín FJ. Sirtuin activators and inhibitors. Biofactors 2012; 38(5): 349-59.
[http://dx.doi.org/10.1002/biof.1032] [PMID: 22730114]
[42]
Jęśko H, Wencel P, Strosznajder RP, Strosznajder JB. Sirtuins and their roles in brain aging and neurodegenerative disorders. Neurochem Res 2017; 42(3): 876-90.
[http://dx.doi.org/10.1007/s11064-016-2110-y] [PMID: 27882448]
[43]
Albani D, Polito L, Batelli S, et al. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1-42) peptide. J Neurochem 2009; 110(5): 1445-56.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06228.x] [PMID: 19558452]
[44]
Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A. Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. Biochem Pharmacol 2007; 73(4): 550-60.
[http://dx.doi.org/10.1016/j.bcp.2006.11.003] [PMID: 17147953]
[45]
Chao J, Yu MS, Ho YS, Wang M, Chang RC. Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic Biol Med 2008; 45(7): 1019-26.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.07.002] [PMID: 18675900]
[46]
Blanchet J, Longpré F, Bureau G, et al. Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(5): 1243-50.
[http://dx.doi.org/10.1016/j.pnpbp.2008.03.024] [PMID: 18471948]
[47]
Zhang A, Wang H, Qin X, Pang S, Yan B. Genetic analysis of SIRT1 gene promoter in sporadic Parkinson’s disease. Biochem Biophys Res Commun 2012; 422(4): 693-6.
[http://dx.doi.org/10.1016/j.bbrc.2012.05.059] [PMID: 22613205]
[48]
Mudò G, Mäkelä J, Di Liberto V, et al. Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol Life Sci 2012; 69(7): 1153-65.
[http://dx.doi.org/10.1007/s00018-011-0850-z] [PMID: 21984601]
[49]
Wu Y, Li X, Zhu JX, et al. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neurosignals 2011; 19(3): 163-74.
[http://dx.doi.org/10.1159/000328516] [PMID: 21778691]
[50]
McLean PJ, Klucken J, Shin Y, Hyman BT. Geldanamycin induces Hsp70 and prevents α-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 2004; 321(3): 665-9.
[http://dx.doi.org/10.1016/j.bbrc.2004.07.021] [PMID: 15358157]
[51]
Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ. Hsp70 reduces α-synuclein aggregation and toxicity. J Biol Chem 2004; 279(24): 25497-502.
[http://dx.doi.org/10.1074/jbc.M400255200] [PMID: 15044495]
[52]
Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 2009; 323(5917): 1063-6.
[http://dx.doi.org/10.1126/science.1165946] [PMID: 19229036]
[53]
Watanabe S, Ageta-Ishihara N, Nagatsu S, et al. SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. Mol Brain 2014; 7(1): 62.
[http://dx.doi.org/10.1186/s13041-014-0062-1] [PMID: 25167838]
[54]
Chen X, Wales P, Quinti L, et al. The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson’s disease but not amyotrophic lateral sclerosis and cerebral ischemia. PLoS One 2015; 10(1): e0116919.
[http://dx.doi.org/10.1371/journal.pone.0116919] [PMID: 25608039]
[55]
Guan Q, Wang M, Chen H, Yang L, Yan Z, Wang X. Aging-related 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurochemial and behavioral deficits and redox dysfunction: improvement by AK-7. Exp Gerontol 2016; 82: 19-29.
[http://dx.doi.org/10.1016/j.exger.2016.05.011] [PMID: 27235848]
[56]
Hasegawa T, Baba T, Kobayashi M, et al. Role of TPPP/p25 on α-synuclein-mediated oligodendroglial degeneration and the protective effect of SIRT2 inhibition in a cellular model of multiple system atrophy. Neurochem Int 2010; 57(8): 857-66.
[http://dx.doi.org/10.1016/j.neuint.2010.09.002] [PMID: 20849899]
[57]
Krey L, Lühder F, Kusch K, et al. Knockout of silent information regulator 2 (SIRT2) preserves neurological function after experimental stroke in mice. J Cereb Blood Flow Metab 2015; 35(12): 2080-8.
[http://dx.doi.org/10.1038/jcbfm.2015.178] [PMID: 26219598]
[58]
Narayan N, Lee IH, Borenstein R, et al. The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature 2012; 492(7428): 199-204.
[http://dx.doi.org/10.1038/nature11700] [PMID: 23201684]
[59]
Liu J, Wu X, Wang X, et al. Global gene expression profiling reveals functional importance of Sirt2 in endothelial cells under oxidative stress. Int J Mol Sci 2013; 14(3): 5633-49.
[http://dx.doi.org/10.3390/ijms14035633] [PMID: 23478437]
[60]
Salvatori I, Valle C, Ferri A, Carrì MT. SIRT3 and mitochondrial metabolism in neurodegenerative diseases. Neurochem Int 2017; 109: 184-92.
[http://dx.doi.org/10.1016/j.neuint.2017.04.012] [PMID: 28449871]
[61]
Lee J, Kim Y, Liu T, et al. SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease. Aging Cell 2018; 17(1): e12679.
[http://dx.doi.org/10.1111/acel.12679] [PMID: 29130578]
[62]
Yang W, Zou Y, Zhang M, et al. Mitochondrial Sirt3 expression is decreased in APP/PS1 double transgenic mouse model of Alzheimer’s disease. Neurochem Res 2015; 40(8): 1576-82.
[http://dx.doi.org/10.1007/s11064-015-1630-1] [PMID: 26045440]
[63]
Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 2017; 16(1): 4-16.
[http://dx.doi.org/10.1111/acel.12538] [PMID: 27686535]
[64]
Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E. Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1α. Neurobiol Dis 2013; 51(1): 72-81.
[http://dx.doi.org/10.1016/j.nbd.2012.07.004] [PMID: 22819776]
[65]
Lloret A, Beal MF. PGC-1α, Sirtuins and PARPs in Huntington’s disease and other Neurodegenerative conditions: NAD+ to rule them all. Neurochem Res 2019; 44(10): 2423-34.
[http://dx.doi.org/10.1007/s11064-019-02809-1] [PMID: 31065944]
[66]
Someya S, Yu W, Hallows WC, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010; 143(5): 802-12.
[http://dx.doi.org/10.1016/j.cell.2010.10.002] [PMID: 21094524]
[67]
Tao R, Coleman MC, Pennington JD, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010; 40(6): 893-904.
[http://dx.doi.org/10.1016/j.molcel.2010.12.013] [PMID: 21172655]
[68]
Luo H, Mu WC, Karki R, et al. Mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome regulates the functional deterioration of hematopoietic stem cell aging. Cell Rep 2019; 26(4): 945-954.e4.
[http://dx.doi.org/10.1016/j.celrep.2018.12.101] [PMID: 30673616]
[69]
Kim HS, Patel K, Muldoon-Jacobs K, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010; 17(1): 41-52.
[http://dx.doi.org/10.1016/j.ccr.2009.11.023] [PMID: 20129246]
[70]
Vazquez BN, Thackray JK, Simonet NG, et al. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. EMBO J 2016; 35(14): 1488-503.
[http://dx.doi.org/10.15252/embj.201593499] [PMID: 27225932]
[71]
Mohrin M, Shin J, Liu Y, et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 2015; 347(6228): 1374-7.
[http://dx.doi.org/10.1126/science.aaa2361] [PMID: 25792330]

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