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Yalcin G. J Neurol Neuromedicine (2018) 3(1): 13-20 Neuromedicine www.jneurology.com www.jneurology.com Journal of Neurology & Neuromedicine

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Sirtuins and Neurodegeneration Gizem Yalcin Department of Medical Biology, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey

Article Info ABSTRACT

Article Notes are highly conserved NAD+-dependent connected to an Received: January 29, 2017 increasing set of biological processes. These enzymes have attracted major interest Accepted: February 23, 2018 because of their roles in age-related diseases. Sirtuins are implicated in various *Correspondence: biological pathways related to stress response, mitochondrial dysfunction, oxidative Dr. Gizem Yalcin stress, protein aggregation and inflammatory processes that are intertwined with Department of Medical Biology, Faculty of Medicine; age-related neurodegenerative diseases. Adnan Menderes University, 09100, Aydin, Turkey, Email: [email protected]

© 2018 Yalcin G. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License Introduction The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to its prominent

Keywords: 1 Sirtuins 1984 in Neurodegeneration role in many cellular processes.Saccharomyces The first cerevisiae (Sir2)) was discovered in Mitochondria in C. elegans3 ; however, interest didD. notmelanogaster begin until24 an effect on life span Disease was observed, in yeast ( . Subsequent studies and then the fruit fly, proved successful in corroborating the effect of increased lifespan. More specifically, the effect of increasedC. elegans lifespan in the fruit fly was correlatedD. melanogaster with calorie restriction5. (CR). Afterwards, it was shown that+-dependent Sir2 extends deacetylases longevity minimally6 at best in and the role of Sir2 in is controversial7. Once Sirtuins were recognized as NAD , and then implicated in silencing and the metabolic pathways the enzymatic functions of sirtuins were elucidated, sirtuins ability to extend life span were shown to involve similar pathways as those of CR. However, the literature regarding the role of yeast, fly and worm sirtuins in CR is controversial. On the other hand, 8 mammalian. sirtuins were found to have various functions in the , , , , and There are seven homologs (SIRT1-7) with different enzymatic activities and localizations in the mammalian cell. SIRT1, -6, and -7 reside primarily in the nucleus and have direct effects on 9 nuclear transcription of involved in metabolism; however SIRT1 shuttles to the cytoplasm when required to act on cytoplasmic9 targets . SIRT1 is highly expressed in 10 the adult with high levels in the cortex, consideredhippocampus, a nuclear cerebellum protein and11 hypothalamus . There are lower levels of alsoSIRT1 located in white in cytoplasm matter .9 SIRT1,12 is primarily expressed in neurons and . However, studies have shown that it is to the nucleus13 . SIRT2 is cytoplasmic and deacetylates and transcription factors that shuttle from the cytoplasm . SIRT2 is expressed primarily in oligodendrocytes and plays a role in sheath formation as well as oligodendroglial

Page 13 of 20 Yalcin G. J Neurol Neuromedicine (2018) 3(1): 13-20 Journal of Neurology & Neuromedicine differentiation14 36 that induces . SIRT3-5 resides in the mitochondrial overexpression found that Aβ toxicity in microglia was matrix and regulates various enzymes in the tricarboxylic reduced via inhibition of NF?B signaling acid and urea cycles,+ oxidative12 phosphorylation and reactive inflammation. -dependent that 37 oxygen species production . One study suggests that SIRT315 translocates to the mitochondria upon cellular stress . CR was shown to attenuate Alzheimer’s disease is a nuclear NAD typeline35 brain amyloidosis in Squirrel monkeys and was . A recent subsequently studied in the APPswe/PSEN1dE9 mouse SIRT6 and SIRT7 are localized to the nucleus, being12 present16 . . The research suggested that attenuation of beta- in heterochromatin and nucleoli, respectively in mouse neurons in vitro amyloid content in the brain during CR can be reproduced studySIRT1’s showed role thatin Neurodegeneration SIRT6 regulates lifespan in male mice by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, SIRT1 is the most extensively studied sirtuin among all known in part for its role in the inhibition of the non- sirtuins. SIRT1 was subsequently studied as a mediator of amyloidogenic α-secretase processing of the APP. These CR, a dietary regimen aimed at reducing caloric intake by results demonstrated for the first time a role for SIRT1 20-30% without malnutrition. CR was previously shown to . A recent study demonstrated in the brain as a novel mechanism through which CR may slow down the aging process,17-22 increasing health and lifespan influence inAD vitro amyloid neuropathology. in several animal models . These phenotypes of that hypothalamic overexpression23 of SIRT1 extends In an work using N2a cells expressing human longevitythe dorsomedial and delays and lateralaging in hypothalamic mice nuclei. Swedish APP mutation (N2aSwe), it was 31 shown that mice are achieved by increased neural activity observed in overexpressing SIRT1 resulted in a significant increase in ADAM10 and sAPPa levels in this cell type . Cilostazol (OPC-13013, 6-[4-(1-cyclohexyl-1H-te- trazol-5-yl) Aging is the major risk factor for the development of butoxy]-3,4-dihydro-2-[1H]-quinolinone) was previously46 neurodegenerative diseases. SIRT1 orchestrates different shown to increase intracellular cyclic AMP (cAMP) levels stress response pathways. More explicitly, SIRT124 targets25 via inhibiting type III phosphodiesterase . In this multiple transcriptional26 regulators, such as , FOXO3 study, cilostazol was demonstrated to enhance the protein and NFκB . Since SIRT1 is also important in regulating expressions of RARb and ADAM10. In addition, ADAM10 mitochondrial function, it is expected that some of the elevation induced by cilastazol was significantly attenuated protective roles of SIRT1 against neurodegenerative by LE135 (a RARb inhibitor), sirtinol (SIRT1 inhibitor), diseasesSIRT1’s might role in be Alzheimer’s through its effects Disease in mitochondria. and RARb-gene silencing. The authors conclude that the increase in the levels of ADAM10/a-secretase activity and the reduction in the intracellular Ab accumulation, which31. Aging population carries a significant amount of are based on the cilostazol-stimulated SIRT1-linked RARb neurodegenerative disease, due to increased life expectancy. activation, ameliorate AD-associated neurodegeneration The most common serious neurodegenerative disorder In N2aSwe cells, increased Ab accumulation was andis Alzheimer’s is the leading disease cause (AD)of dementia causing among severe the cognitive elderly and accompanied by increased Ac-tau and P-tau levels together behavioral deficits. AD affects 35 million people worldwide27 with elevated P300 and38 GSK3b P-Tyr216 expression; their . Aβ expressions were significantly reduced by cilostazol and is the product of the proteolytic cleavage of the amyloid-β resveratrol treatments . This study showed that increased protein precursor (AβPP) into 38, in 40, vitro or and 42 amino in viv28o acidand neurodegenerationcAMP-dependent 38 protein. kinase-linked CK2/ SIRT1 peptides and is viewed as the toxic mediator of AD . Aβ expression by cilostazol may suppress the tau-related oligomerization is toxic to neurons Another study demonstrated that ap produces synaptic dysfunction, calcium29 dysregulation, ) is the primary component of the senile olipoprotein E oxidative stress, and neuroinflammation30. . Moreover, Aβ 42 ε4 allele (ApoE) significantly39 reduces the ratio of soluble (specifically Aβ amyloid precursor protein alpha (sAPPa) to Ab and also plaques that develop in the of AD decreases SirT1 expression . It was also shown that Ab The mounting evidence for the implications of the reduces SIRT1 expression, triggers Tau phosphorylation39. Therapeutic and effects of SIRT1 in AD initially came from research+ or APP phosphorylation. Additionally, programmed cell death primarily focused on thein effects vitro of SIRT1 overexpression is induced as a result of Ab accumulation mediated by small molecule modulators, such as NAD up-regulation of SIRT1 might provide opportunities for the resveratrol. For example, , both were found to reduce32 analysisamelioration into this of Alzheimer’s-disease-type aspect is necessary if any neuropathology progress is to Aβ oligomers in a concentration33-35 dependent manner . In through inhibition of amyloidogenesis. Ultimately, further addition, both small molecule modulators were found to ameliorate oxidative stress . Another study with SIRT1 be made.

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46 Other transgenic mice studies include a p25 transgenic was shown to attenuate oxidative stress induced by mouse, which overexpresses the cdk5-activating human40. Tau the parkinsonian mimetic 6-hydroxydopapamine47. The authors of p25 protein thereby exhibiting tau hyperphosphorylation as well as the controversial treatment for PD, L-3,4- and neurodegeneration with features similar to AD dihydroxyphenylalanine (L-dopa) is a -binding protein found in high content in these studies suggest that the properties of neurons and is responsible for the assembly and stability resveratrol are involved in its attenuation of oxidative stress of microtubules. Hyperphosphorylation of the tau protein as the neuroprotective effect, rather than investigating leads toward tangles in an ordered fashion such as paired SIRT1 activation. Moreover, resveratrol48 exhibited a helices and straight filaments. These self-assembled neuroprotective effect on dopaminergic neurons in tangles are implicated in the pathogenesis of AD as well midbrain slice culture from multiple insults . In this study, as other taupathies. Cyclin-dependent kinase 5 (cdk5)38. it was determined that the neuroprotective effect was and its regulatory subunit p35 have important roles in the indeed, void of SIRT1 activation because SIRT1 inhibitors development of the mammalian central nervous system did not attenuate the protective resveratrol effects. Proteolytic cleavage of p35 yields p25, which then activates Studies performed so far suggests that SIRT1 cdk5. Accumulation of p25 is a hallmark of neurodegenerative may be a pharmacological target in the treatment of disease. In a mouse model (cdk5-activating p25), injection neurodegenerative diseases by deacetylating different of the SIRT1-activating polyphenol resveratrol resulted 41 in. target proteins. However, additional studies are essential less hippocampal degeneration, less cognitive deficit, and to substantially prove SIRT1 provides a molecular basis of reduced of SIRT1 substrates PGC-1α and p53 protection. For example, one study, which used the well- Additionally, when SIRT1 was directly overexpressed in inestablished no protection 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine49 the of these mice using a lentiviral vector, the (MPTP) model of PD in SIRT1 transgenic mice, resulted effects of resveratrol injections were corroborated. in that tau is acetylated at multiple residues and . Neuron-specific enolase (NSE) SIRT1 Tau and SIRT1 have previously shown a relationshipvia transgenic mice were generated to overexpress human deacetylation SIRT1 in neurons. Overexpression48. of SIRT1 did not have SIRT1 regulates42 the level of phosphorylated tau any neuroprotective effects against the neuronal damage . When tau is acetylated by the histone SIRT1’sinduced by role ischemia in Huntington’s or MPTP Disease acetyltransferase, p300, the breakdown of tau is inhibited. - SIRT1 inhibition was shown to increase tau levels thereby reducedincreasing neuronal phosphorylated cell death 39 tau.. In summary, degradation Huntington’s disease (HD) is a neurodegenerative dis- of phosphorylated tau improved cognitive function and easeed polyglutamine that affects four repeat to seven in huntingtin individuals (HTT) per protein. 100,000. HD SIRT1’role in Parkinson’s disease is a fatal neurodegenerative disorder caused by an expand

In a mouse model of HD, brain-specific knockout Parkinson’s disease (PD) is another progressive of SIRT1 results in exacerbation of brain 51 pathology, neuronsneurodegenerative in the substantia disorder affectingnigra pars the centralcompacta nervous whereas overexpression of SIRT1 improved survival, system. The neuropathology involves loss of dopaminergic neuropathologyto mediate neuroprotection and the expression from ofmutant BDNF [ HTT.]. SIRT1 The , and deacetylase activity was shown to directly target neurons its symptoms include muscle rigidity, bradykinesia, resting tremor and postural43 instability, amongst others. neuroprotective effect of SIRT1 requires the presence Cytoplasmic inclusions called Lewy bodies (LB) containing of CREB-regulated transcription coactivator 1 (CRTC1), Althoughthe protein the α-synuclein reason for the, some neuronal proteasomal cell loss and still lysosomal remains a brain-specific modulator of CREB activity. Under subunits have been found on histological analysis of PD. normal conditions, SIRT1 deacetylates and activates CRTC1 by promoting its dephosphorylation and its elusive, misfolding, oligomerization and α-synuclein interaction with CREB. BDNF was identified as a key aggregation have been implicated44 in the neuropathology target of SIRT1 and CRTC1 transcriptional activity in both of PD and parkinsonian plus disorders such as multiple normal and HD neurons. Mutantin vitro HTT and interferes in vivo50 with the systems atrophy (MSA) . Studies of PD models and the CRTC1-CREB interaction to repress BDNF transcription, functions of genes implicated in inherited forms of PD dopaminergic neuronal cell death: (i) mitochondrial and SIRT1 rescues this defect. . Together, have looked at two different possibilitiesi) leadingmisfolding toward and these findings show a 52 neuroprotective role for SIRT1 in aggregation of proteins45. mammalianSIRT1’s role HD in models ALS dysfunction and oxidative stress, and (i

In other cell culture studies, dietary resveratrol Loss of neurons with age is also seen in amyotrophic

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lateral sclerosis (ALS). The underlying causes of response to environmental stimuli is likely to be critical denervation of the neuromuscular junction and eventual to prevent aging and age-dependent diseases, including motor neuron death in ALS have not been resolved. SIRT2’scancer, neurodegenerative role in Parkinson’s diseases Disease and diabetes. The superoxide dismutase 1 (SOD1)(G93A) mouse is a frequently used animal model of ALS. As SIRT2 inhibition, pharmacologically or genetically, was mentioned earlier, resveratrol, a polyphenolicvia modulation molecule of p53 in vitro and in vivo found to be beneficial in the rescue of alpha-synuclein acetylationthat enhances38 SIRT1 activity, improved motor function and survival in the SOD1 mouse model toxicity in both models of Parkinson’s . Manipulation of SIRT1 deacetylase activity Disease (PD). A potent inhibitor of SIRT257 was shown to had effects at the protein level in healthy aging organisms; inhibit alpha-synucleinvia toxicity and modified inclusion however,53 resveratrol treatment did not lead to functional morphology in a cellular model of PD . Genetic inhibition improvement or increased longevity in a mouse model of SIRT2 small interfering RNA similarlyin vitrorescued and alpha- in a of ALS . In a similar mouse model, region specific changes synuclein toxicity. In addition, the inhibitors protected in the immunoreactivity of SIRT1 expression in the central against dopaminergic cell death both nervous system was observed. SIRT1 increases in cerebral Drosophila model of PD. In addition, the interaction between oligomeric alpha-synuclein and acetylated microtubules cordcortical54. pyramidal cells, hippocampal pyramidal cells of area CA1-3 and dentate gyrus cells, thalamus, and spinal was investigated as a source of neurodegeneration. SIRT2 inhibition was shown to increase microtubule-dependent transport of neurotoxic57. alpha-synuclein oligomers to The role that SIRT1 activation plays in the pathogenesis the nucleation aggregation site, facilitating formation of of ALS remains unclear;55 however, via activating SIRT1, inclusions called LB resveratrol was shown to protect against neurodegeneration in a cell model of ALS . SIRT1 expression was found to be It was recently shown that SIRT2 in the brain enhanced much lower in the mutant (SOD1)(G93A)-bearing VSC4.1 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-59 cells compared to (SOD1)(wt) cells when both were induced nigrostriatal damage via deacetylating FOXO3a and cultured in low-serum medium, indicating the involvement activating Bim . MPTP is a dopaminergic neurotoxin that of SIRT1 activation defects in the pathogenesis of ALS under replicates most of the clinical features of PD and produces energetic stress. Further investigation revealed that systemica reliable administration and reproducible57 lesion of the nigrostriatal resveratrol had a dose-dependent protective effect on dopaminergic pathway and 57 neurodegeneration after its this ALS cell model. This further demonstrated a role for . Chronic administration of MPTP SIRT1 activation in the protection of neuronal cells from induces lesion via apoptosis . It was shown that SIRT2 degeneration. These findings suggest that resveratrol can deacetylates Foxo3a, increases RNA and protein levels protect the ALS cell model from mutant SOD1-mediated of Bim, a proapoptotic factor, and as a result, enhances toxicity through up-regulating the expression of SIRT1, apoptosis in the MPTP model of PD. Neurodegeneration which might represent a potential therapeutic target for reductioninduced by of chronic apoptosis MPTP due regimen to an increase is prevented in acetylation by genetic of SIRT2’spreventing role the in motor Neurodegeneration neuron degeneration in ALS patients. deletion of SIRT2 in mouse. Deletion59. of SIRT2 lead to the

Foxo3aSIRT2’s and role a decrease in Huntington’s in Bim levels Disease SIRT2 is an oligodendroglial cytoplasmic protein and localized to the outer and juxtanodal loops in the myelin sheath. Among14 cytoplasmic proteins of OLN-93 The molecular pathogenesis of Huntington’s disease oligodendrocytes, alpha-tubulin is the main substrate of (HD) is complex and many mechanisms and cellular SIRT2 deacetylase . There exists a counterbalancing role processes have been proposed as potential sites of toof SIRT2oligodendroglia against a facilitator has important effect of tubulinimplications acetylation for therapeutic intervention. Previous studies in invertebrate on oligodendroglial differentiation. SIRT2 availability onand disease cell cultureprogression HD models have suggested that inhibition of SIRT2 could60,61 have beneficial consequences myelinogenesis, myelin-axon interaction, and brain aging. . SIRT2 has been proposed to In addition to ?-tubulin14 and substrates, SIRT2 deacetylate α-tubulin, histone H4 K1658 and to regulate deacetylates forkhead transcription factors of class O, cholesterol biogenesis, a pathway, which is dysregulated FOXO1 and FOXO3 . Since FOXO transcription factors are in HD patients and HD mouse models . The distribution involved in several cellular processes, including yet not and function of the SIRT2 microtubule deacetylase in processeslimited to56 DNA repair, , apoptosis, metabolism differentiated, postmitotic neurons were investigated and and aging, SIRT2 has been initially investigated in these it was determined that expression of specific isoforms of . The effective control of FOXO activity in SIRT2 in the mammalian central nervous system exhibits

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65 age-dependent accumulation in the mouse brain and deacetylation activity . A recent study showed66. The that study SIRT3 also . Furthermore, endogenous SIRT2 expression localizes to the mitochondria, does not exist in nucleus and correlates with reduced α-tubulin acetylation in primary init is mitochondria a proteolytically modified deacetylase mouse cortical neurons; therefore, it is postulated. that emphasizes that66,67 SIRT3 does the majority of deacetylation brain-enriched species of SIRT2 may function62 as the . A number of targets were identified microtubuleAn in vivo deacetylases in mature neurons for SIRT3; however, only a handful of substrates were described for SIRT4 and SIRT5. Mitochondrial dysfunction study, SIRT2 was reduced or ablated to further is associated with age-related disorders such as metabolic explore the function of SIRT263 and to assess whether SIRT2 syndrome, cancer and neurodegeneration. The role of loss has a beneficial impact on disease progression in the had no effect mitochondrial sirtuins in brain and their relation to R6/2 mouse model of HD . The reduction or loss of SIRT2 neurodegeneration is not broadly studied except for a few on the acetylation of α-tubulin or H4K16 recent in vivo studies using toxins such as kainic acid and or on cholesterol biosynthesis in the brains of wild type MPTP. mice. In addition, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery SIRT3 was shown to attenuate MPTP-induced of physiological and behavioral tests. Therefore, it was nigrostriatal damage in mice [68]. SIRT3 KO mice displayed concluded that SIRT2 inhibition does not modify disease increased degeneration compared to wild type mice after progression60. in the R6/2 mouse model of HD and SIRT2 MPTP administration. Decreased levels of superoxide inhibition should not be prioritized as a therapeutic option dismutase 2 (SOD2), a specific mitochondrial antioxidant Another for HD in vivo enzyme, and glutathione68 peroxidase expression was detected in MPTP-induced SIRT3 KO mice compared to model utilizes the efficacy of a brain- wild-type controls . Therefore, it was concluded that SIRT368 permeable SIRT2 inhibitor in two separate genetic mouse . A might be protective in MPTP-induced neurodegeneration models of HD. It was reported that compound treatment via improving antioxidant capacity in mitochondria resulted in improved motor function, extended survival,64 similar study was conducted using SIRT5 KO mice. MPTP- and reduced brain atrophy with reduction of aggregated induced nigrostriatal degeneration was elevated69 in SIRT5 mutant huntingtin (a hallmark of HD pathology) . In . KO mice together with a larger decrease in the expression addition, genetic or pharmacologic inhibition of SIRT2 in a level of SOD2 compared to wild type controls striatal neuronal model of HD resulted61 in changes including significant down-regulation of the RNAs SIRT4 was shown to have different physiological roles responsible for sterol biosynthesis . Mutant huntingtin in various tissues but its role in brain was unexplored. 70A. fragments increases sterols in neuronal cells; therefore, recent study showed that SIRT4 is up-regulated in brain manipulation of sterol biosynthesis at the transcriptional in response to treatment with kainic acid, an excitotoxin level would prove beneficial. Glutamate transport keeps low extracellular levels of glutamate in the brain to prevent excitotoxicity that leads Most of the studies showed that the inhibition of SIRT2 to neurodegeneration and inefficient neurotransmission. is beneficial for HD except the study that used R6/2 as a SIRT470 KO mice displayed severe seizure phenotypes model [60]. R6/2 mouse model displays aggressive HD acid compared to wild type mice after exposure to kainic phenotype, therefore additional studies should be designed . Deletion of SIRT4 also leads to reduced glutamate where different HD mouse models are utilized. The outcome transporter expression in brain after kainic acid of the deletion of SIRT2 in these mouse models should be administration. This study showed70 a novel stress response analyzed in order to assess the role of SIRT2 in HD. . role for SIRT4 in maintaining efficient glutamate transport In summary, in all the disease models studied, inhibition SIRT6,and preventing SIRT7 excitotoxicity and Neurodegeneration of SIRT2 seems to have beneficial effects by deacetylating different targets. Therefore, inhibiting the activity of this Mitochondrialenzyme might be Sirtuins effective and in designing Neurodegeneration effective therapies. SIRT6 is a nuclear enzyme known to deacetylate histone H3-lysine 9 (H3K9). In71, previous72 studies, SIRT6 was found to promote longevity . Due to the phenotype observed Three of the mammalian sirtuins, SIRT3, SIRT4 and functionsin SIRT6 knockout mice, this protein is also thought to SIRT5 are localized65 in mitochondria, which are the major regulate DNA72 base excision repair (BER) and metabolic organelles responsible for energy production, balance and . A more recent study showed73 that SIRT6 metabolism . SIRT3 was shown to have strong deacetylase regulates the stability of Tau protein and the lack of SIRT6 activity. On the other hand, SIRT4 has adenosine increases hyperphosrylated tau levels . Moreover, RNA diphosphate (ADP)–ribosylation activity, and SIRT5 has and protein levels of SIRT6 were found to be decreased desuccinylase and demalonylase activity in addition to weak in Alzheimer’s disease patients. Therefore, SIRT6 and its

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downstream targets could be targeted for therapeutical might be beneficial against neurodegenerative diseases. strategies in neurodegenerative diseases. It is extremely important to develop selective activators 74 different functions in different cellular compartments. nucleolus or inhibitors that target a specific sirtuin since they have SIRT7 is the least characterized sirtuin and found in . It interacts75 with rDNA and regulates RNA Pol human tumors Additionally, the level of sirtuins in specific areas of the I [74]. SIRT7 was76 shown to be overexpressed in many proto-oncogene brain may hold a prognostic value for the detection or and recent studies identified SIRT7 as a diagnosis of the diseases. However, the best modulators of . However, SIRT7 is largely unexplored sirtuins against age-related disorders can only be designed for neurodegenerative diseases and brain. Similar if we understand the molecular mechanisms underlying expression could be modulated in cell and animal models Referencestheir effects in neurodegenerative diseases and brain. of neurodegenerative diseases, similar to the previous 1. studies conducted for other sirtuins. SIRT7 is also expected Conclusionto have major functions in neuronal pathways and diseases. Shore D, Squire M, Nasmyth KA. Characterization of two genes required for the position-effect control of yeast mating-type genes. Embo J. 1984; 3: 2817-2823. The functions of sirtuins in the brain are still unknown; 2. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different however, published studies show that they have important 3. mechanisms. Genes Dev. 1999; 13: 2570-2580. roles in neurodegenerative diseases. Substrates of sirtuins Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends are molecules that take part in the fundamental cellular 4. lifespan in Caenorhabditis elegans. Nature. 2001; 410: 227-230. pathways and are crucial to the biology of the organism. 101:Rogina 15998-16003. B, Helfand SL. Sir2 mediates longevity in the fly through a Investigating the roles of sirtuins in neurodegeneration not pathway related to calorie restriction. Proc Natl Acad Sci U S A. 2004; 5. only elucidates ( 1). whether these molecules are of importance et al. therapeutically but also identifies their novel functions in Burnett C, Valentini S, Cabreiro F, Absence of effects of Sir2 brain Figure overexpression on lifespan in C. elegans and Drosophila. Nature. 6. 2011; 477: 482-485. Although all seven mammalian sirtuins are expressed Imai S, Armstrong CM, Kaeberlein M, et al. Transcriptional silencing in the brain, only the roles of SIRT1 and SIRT2 in and longevity protein Sir2 is an NAD-dependent histone deacetylase. neurodegeneration were extensively studied (Figure 1). 7. Nature. 2000; 403: 795-800. The findings show that SIRT1 activation generally displays Guarente L. Sir2 links chromatin silencing, metabolism, and aging. a protective role against neurodegenerative diseases; 8. Genes Dev. 2000; 14: 1021-1026. althoughwhereas, they SIRT2 share inhibition a common or deletion catalytic shows domain. a positive They Donmez G, Guarente L. Aging and disease: connections to sirtuins. outcome. These two enzymes seem to be quite different 9. Aging Cell. 2010; 9: 285-290. et al. Tanno M, Sakamoto J, Miura T Nucleocytoplasmic shuttling of have different targets and they are located in different the NAD+-dependent histone deacetylase SIRT1. J Biol Chem. 2007; 10. subcellular locations. In light of the studies conducted, 282: 6823-6832. et al. we can conclude that activating SIRT1 and inhibiting Ramadori G, Lee CE, Bookout AL, Brain SIRT1: anatomical SIRT2 seem to be beneficial for the organism. On the other distribution and regulation by energy availability. J Neurosci. 2008; 11. 28: 9989-9996. hand, deletion of mitochondrial sirtuins in mice display increased degeneration in brain after administration of Sakamoto J, Miura T, Shimamoto K, et al. Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic toxins. Therefore, designing pharmacological activators or mouse heart and brain. FEBS Lett. 2004; et al.556: 281-286. inhibitors for sirtuins is a crucial research area since they 12. Michishita E, Park JY, Burneskis JM, Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT 13. proteins. Mol Biol Cell. 2005; 16: 4623-4635. et al.

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