Sirtuin 3 expression in the context of Relapsing Remitting Multiple Sclerosis
Keywords:
Multiple Sclerosis, MS, Sirtuin, Sirt3, RRMS, NeuroinflammationAbstract
Multiple sclerosis (MS) is a debilitating disease that attacks the myelin sheath surrounding neurons in the central nervous system resulting in focal demyelinated lesions. This process is immune-mediated in nature and is thought to arise following inflammatory and metabolic alterations leading to loss of the myelin sheath. Following this, axons in the afflicted areas may recover and remyelinate or undergo axonal loss leading to eventual neurodegeneration. Current knowledge of the mechanisms involved in lesion formation and neuronal outcomes is limited. A relatively recently identified family of proteins, the sirtuins, have been found to be strongly implicated in inflammation and aging throughout the body. While some work has identified alterations in sirtuins 1 and 2 within animal models and MS samples, no such investigations have examined the related sirtuin 3 (Sirt3) protein. In our current study, we examined Sirt3 expression in MS lesions from post-mortem tissue as well as mRNA levels within CD14+ cells isolated from MS patients and controls. We found reduced Sirt3 expression within MS lesions and trends towards reduced Sirt3 mRNA levels in females as well as MS patients. Overall, our work supports the hypothesis that Sirt3 plays a role in MS, however, further studies are needed to identify the CNS distribution of Sirt3 in MS patients, how Sirt3 alterations impact CD14+ cells in MS, and whether Sirt3 may play a role in the sex differences observed in MS.References
Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816. doi:10.1177/1352458520970841
Kamińska J, Koper OM, Piechal K, Kemona H. Multiple sclerosis - etiology and diagnostic potential. Postepy Hig Med Dosw (Online). 2017;71:551-563. doi:10.5604/01.3001.0010.3836
Klein R, Burton J. The Gender Divide in Multiple Sclerosis: A Review of the Environmental Factors Influencing the Increasing Prevalence of Multiple Sclerosis in Women (P4.024). Neurology. 2014;82(10 Supplement).
Sand IK. Classification, diagnosis, and differential diagnosis of multiple sclerosis. Curr Opin Neurol. 2015;28(3):193-205. doi:10.1097/WCO.0000000000000206
Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011;93(1):1-12. doi:10.1016/j.pneurobio.2010.09.005
Nicholas R, Rashid W. Multiple Sclerosis - Clinical Evidence Handbook. Am Fam Physician. 2013;87(10):712-714. https://www.aafp.org/afp/2013/0515/p712.html. Accessed December 5, 2019.
Feinstein A, Freeman J, Lo AC. Treatment of progressive multiple sclerosis: What works, what does not, and what is needed. Lancet Neurol. 2015;14(2):194-207. doi:10.1016/S1474-4422(14)70231-5
Hart FM, Bainbridge J. Current and emerging treatment of multiple sclerosis. The American journal of managed care. https://www.ajmc.com/journals/supplement/2016/cost-effectiveness-multiple-sclerosis/cost-effectiveness-multiple-sclerosis-current-emerging-treatment. Published 2016. Accessed December 5, 2019.
Frohman EM, Shah A, Eggenberger E, Metz L, Zivadinov R, Stüve O. Corticosteroids for Multiple Sclerosis: I. Application for Treating Exacerbations. Neurotherapeutics. 2007;4(4):618-626. doi:10.1016/j.nurt.2007.07.008
Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clin Cases. 2015;3(7):545. doi:10.12998/wjcc.v3.i7.545
van der Poel M, Ulas T, Mizee MR, et al. Transcriptional profiling of human microglia reveals grey–white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun. 2019;10(1). doi:10.1038/s41467-019-08976-7
Kuhlmann T, Ludwin S, Prat A, Antel J, Brück W, Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13-24. doi:10.1007/s00401-016-1653-y
Banks WA. The blood-brain barrier in neuroimmunology: Tales of separation and assimilation. Brain Behav Immun. 2015;44:1-8. doi:10.1016/j.bbi.2014.08.007
Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45. doi:10.3389/fncel.2013.00045
von Bernhardi R, Heredia F, Salgado N, Muñoz P. Microglia Function in the Normal Brain. In: Advances in Experimental Medicine and Biology. Vol 949. ; 2016:67-92. doi:10.1007/978-3-319-40764-7_4
Fernández-Arjona M del M, Grondona JM, Granados-Durán P, Fernández-Llebrez P, López-Ávalos MD. Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis. Front Cell Neurosci. 2017;11:235. doi:10.3389/fncel.2017.00235
Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional Microglia–Neuron Communication in Health and Disease. Front Cell Neurosci. 2018. doi:10.3389/fncel.2018.00323
Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci. 2017;20(2):136-144. doi:10.1038/nn.4475
Marinelli S, Basilico B, Marrone MC, Ragozzino D. Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission. Semin Cell Dev Biol. 2019;94:138-151. doi:10.1016/J.SEMCDB.2019.05.017
Gosselin D, Skola D, Coufal NG, et al. An environment-dependent transcriptional network specifies human microglia identity. Science (80- ). 2017;356(6344):1248-1259. doi:10.1126/science.aal3222
Melief J, Schuurman KG, van de Garde MDB, et al. Microglia in normal appearing white matter of multiple sclerosis are alerted but immunosuppressed. Glia. 2013;61(11):1848-1861. doi:10.1002/glia.22562
Klein B, Mrowetz H, Barker CM, Lange S, Rivera FJ, Aigner L. Age Influences Microglial Activation After Cuprizone-Induced Demyelination. Front Aging Neurosci. 2018;10. doi:10.3389/fnagi.2018.00278
Airas L, Nylund M, Rissanen E. Evaluation of microglial activation in multiple sclerosis patients using positron emission tomography. Front Neurol. 2018;9(MAR). doi:10.3389/fneur.2018.00181
Krish Chandrasekaran M, Russell JW, Nagalla TK, et al. Multiple SIRT1 Targets Encephalomyelitis through Activation of Protects against Experimental Autoimmune Overexpression of SIRT1 Protein in Neurons. J Immunol Ref. 2013;190:4595-4607.
doi:10.4049/jimmunol.1202584
Guarente L. Sirtuins in aging and disease. In: Cold Spring Harbor Symposia on Quantitative Biology. Vol 72. ; 2007:483-488. doi:10.1101/sqb.2007.72.024
Imai SI, Guarente L. It takes two to tango: Nad+ and sirtuins in aging/longevity control. npj Aging Mech Dis. 2016;2(1). doi:10.1038/npjamd.2016.17
Chen Z, Zhai Y, Zhang W, Teng Y, Yao K. Single nucleotide polymorphisms of the sirtuin 1 (SIRT1) gene are associated with age-related macular degeneration in Chinese han individuals a case-control pilot study. Med (United States). 2015;94(49). doi:10.1097/MD.0000000000002238
Clark SJ, Falchi M, Olsson B, et al. Association of sirtuin 1 (SIRT1) gene SNPs and transcript expression levels with severe obesity. Obesity. 2012;20(1):178-185. doi:10.1038/oby.2011.200
Head PE, Zhang H, Bastien AJ, et al. Sirtuin 2 mutations in human cancers impair its function in genome maintenance. J Biol Chem. 2017;292(24):9919-9931. doi:10.1074/jbc.M116.772566
Jin X, Wei Y, Xu F, et al. SIRT1 promotes formation of breast cancer through modulating Akt activity. J Cancer. 2018;9(11):2012-2023. doi:10.7150/jca.24275
Bosch-Presegué L, Vaquero A. The dual role of sirtuins in cancer. Genes and Cancer. 2011;2(6):648-662. doi:10.1177/1947601911417862
Tang BL. Sirtuins as modifiers of Parkinson’s disease pathology. J Neurosci Res. 2017;95(4):930-942. doi:10.1002/jnr.23806
Planavila A, Iglesias R, Giralt M, Villarroya F. Sirt1 acts in association with PPAR to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovasc Res. 2011;90(2):276-284. doi:10.1093/cvr/cvq376
Michan S, Sinclair D. Sirtuins in mammals: Insights into their biological function. Biochem J. 2007;404(1):1-13. doi:10.1042/BJ20070140
Foolad F, Khodagholi F, Javan M. Sirtuins in Multiple Sclerosis: The crossroad of neurodegeneration, autoimmunity and metabolism. Mult Scler Relat Disord. 2019;34:47-58. doi:10.1016/j.msard.2019.06.004
Inkster B, Strijbis EMM, Vounou M, et al. Histone deacetylase gene variants predict brain volume changes in multiple sclerosis. Neurobiol Aging. 2013;34(1):238-247. doi:10.1016/j.neurobiolaging.2012.07.007
Nimmagadda VK, Bever CT, Vattikunta NR, et al. Overexpression of SIRT1 Protein in Neurons Protects against Experimental Autoimmune Encephalomyelitis through Activation of Multiple SIRT1 Targets. J Immunol. 2013;190(9):4595-4607. doi:10.4049/jimmunol.1202584
Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuro-Ophthalmology. 2010;30(4):328-339. doi:10.1097/WNO.0b013e3181f7f833
McDougald DS, Dine KE, Zezulin AU, Bennett J, Shindler KS. SIRT1 and NRF2 gene transfer mediate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis. Investig Ophthalmol Vis Sci. 2018;59(3):1212-1220. doi:10.1167/iovs.17-22972
Ciriello J, Tatomir A, Hewes D, et al. Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp Mol Pathol. 2018;105(2):175-180. doi:10.1016/j.yexmp.2018.07.008
Prozorovski T, Ingwersen J, Lukas D, et al. Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells. Neurosci Lett. 2019;704:116-125. doi:10.1016/j.neulet.2019.04.007
Jastorff AM, Haegler K, Maccarrone G, et al. Regulation of proteins mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. PROTEOMICS ��� Clin Appl. 2009;3(11):1273-1287. doi:10.1002/prca.200800155
Shi H, Deng H-X, Gius D, Schumacker PT, Surmeier DJ, Ma Y-C. Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet. 2017;26(10):1915-1926. doi:10.1093/hmg/ddx100
Kurundkar D, Kurundkar AR, Bone NB, et al. SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury. JCI Insight. 2019;4(1). doi:10.1172/jci.insight.120722
Liu X, Zhang L, Wang P, et al. Sirt3-dependent deacetylation of SOD2 plays a protective role against oxidative stress in oocytes from diabetic mice. Cell Cycle. 2017;16(13):1302-1308. doi:10.1080/15384101.2017.1320004
Rice CM, Sun M, Kemp K, Gray E, Wilkins A, Scolding NJ. Mitochondrial sirtuins - a new therapeutic target for repair and protection in multiple sclerosis. Eur J Neurosci. 2012;35(12):1887-1893. doi:10.1111/j.1460-9568.2012.08150.x
Park J-H, Delenclos M, Faroqi AH, DeMeo NN, McLean PJ. Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway. bioRxiv. June 2018:357624. doi:10.1101/357624
Gleave JA, Arathoon LR, Trinh D, et al. Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism. Neurobiol Dis. 2017;106:133-146. doi:10.1016/j.nbd.2017.06.009
Rangarajan P, Karthikeyan A, Lu J, Ling EA, Dheen ST. Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. Neuroscience. 2015;311:398-414. doi:10.1016/j.neuroscience.2015.10.048
Cao R, Li S, Yin J, Guo L, Shi J. Sirtuin 3 promotes microglia migration by upregulating CX3CR1. Cell Adh Migr. 2019;13(1):229-235. doi:10.1080/19336918.2019.1629224
Cardona AE, Pioro EP, Sasse ME, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9(7):917-924. doi:10.1038/nn1715
Paolicelli RC, Bisht K, Tremblay M-È. Fractalkine regulation of microglial physiology and consequences on the brain and behavior. Front Cell Neurosci. 2014;8:129. doi:10.3389/fncel.2014.00129
Tegla CA, Azimzadeh P, Andrian-Albescu M, et al. SIRT1 is decreased during relapses in patients with multiple sclerosis. Exp Mol Pathol. 2014;96(2):139-148. doi:10.1016/j.yexmp.2013.12.010
Lim HW, Kang SG, Ryu JK, et al. SIRT1 deacetylates RORγt and enhances Th17 cell generation. J Exp Med. 2015;212(5):607-617. doi:10.1084/JEM.20132378
Blagov A V., Sukhorukov VN, Orekhov AN, Sazonova MA, Melnichenko AA. Significance of Mitochondrial Dysfunction in the Progression of Multiple Sclerosis. Int J Mol Sci. 2022;23(21). doi:10.3390/IJMS232112725
de Barcelos IP, Troxell RM, Graves JS. Mitochondrial Dysfunction and Multiple Sclerosis. Biology (Basel). 2019;8(2). doi:10.3390/BIOLOGY8020037
de Arellano MLB, Pozdniakova S, Kühl AA, Baczko I, Ladilov Y, Regitz-Zagrosek V. Sex differences in the aging human heart: Decreased sirtuins, proinflammatory shift and reduced anti-oxidative defense. Aging (Albany NY). 2019;11(7):1918-1933. doi:10.18632/aging.101881
Panza S, Santoro M, De Amicis F, et al. Estradiol via estrogen receptor beta influences ROS levels through the transcriptional regulation of SIRT3 in human seminoma TCam-2 cells. Tumor Biol. 2017;39(5). doi:10.1177/1010428317701642
Shen H, Holliday M, Sheikh-Hamad D, et al. Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury. Transl Res. March 2021. doi:10.1016/j.trsl.2021.03.015
Pinterić M, Podgorski II, Hadžija MP, et al. Role of sirt3 in differential sex-related responses to a high-fat diet in mice. Antioxidants. 2020;9(2). doi:10.3390/antiox9020174
Published
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work
