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SIRT1 Protects Dopaminergic Neurons in Parkinson’s Disease Models via PGC-1α-Mediated Mitochondrial Biogenesis

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Abstract

SIRT1 is a deacetylase with multiple physiological functions by targeting histones and non-histone proteins. It has been shown that SIRT1 activation is involved in neuroprotection in Parkinson’s disease (PD) models. In the present study, we provided direct evidences showing the neuroprotective roles of SIRT1 in dopaminergic neurons. Our data showed that increased expression of SIRT1 plays beneficial roles against MPP+ insults in SH-SY5Y cells and primary dopaminergic neurons, including increased cell viability, reduced LDH release, improved the mitochondrial membrane potential (MMP), and attenuated cell apoptosis. On the contrary, knockdown of SIRT1 further aggravated cell injuries induced by MPP+. Moreover, mutated SIRT1 without deacetylase activity (SIRT1 H363Y) failed to protect dopaminergic neurons from MPP+ injuries. Mechanistically, SIRT1 improved PGC-1α expression and mitochondrial biogenesis. Knockdown of PGC-1α almost completely abolished the neuroprotective roles of SIRT1 in SH-SY5Y cells. Collectively, our data indicate that SIRT1 has neuroprotective roles in dopaminergic neurons, which is dependent upon PGC-1α-mediated mitochondrial biogenesis. These findings suggest that SIRT1 may hold great therapeutic potentials for treating dopaminergic neuron loss associated disorders such as PD.

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References

  • Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423:181–185

    Article  CAS  Google Scholar 

  • Armstrong MJ, Okun MS (2020) Diagnosis and treatment of parkinson disease: a review. JAMA 323:548–560

    Article  Google Scholar 

  • Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  Google Scholar 

  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015

    Article  CAS  Google Scholar 

  • Buneeva O, Fedchenko V, Kopylov A, Medvedev A (2020) Mitochondrial dysfunction in Parkinson’s disease: focus on mitochondrial DNA. Biomedicines 8

  • Chen H, Ji H, Zhang M, Liu Z, Lao L, Deng C, Chen J, Zhong G (2017) An agonist of the protective factor SIRT1 improves functional recovery and promotes neuronal survival by attenuating inflammation after spinal cord injury. J Neurosci 37:2916–2930

    Article  CAS  Google Scholar 

  • Ciron C, Zheng L, Bobela W, Knott GW, Leone TC, Kelly DP, Schneider BL (2015) PGC-1alpha activity in nigral dopamine neurons determines vulnerability to alpha-synuclein. Acta Neuropathol Commun 3:16

    Article  Google Scholar 

  • Dorsey ER, Bloem BR (2018) The Parkinson pandemic—a call to action. JAMA Neurol 75:9–10

    Article  Google Scholar 

  • Ellis L, Clauser E, Morgan DO, Edery M, Roth RA, Rutter WJ (1986) Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose. Cell 45:721–732

    Article  CAS  Google Scholar 

  • Fang X, Ma J, Mu D, Li B, Lian B, Sun C (2020) FGF21 protects dopaminergic neurons in Parkinson’s disease models via repression of neuroinflammation. Neurotox Res 37:616–627

    Article  CAS  Google Scholar 

  • Gaven F, Marin P, Claeysen S (2014) Primary culture of mouse dopaminergic neurons. J Vis Exp e51751

  • Gleave JA, Arathoon LR, Trinh D, Lizal KE, Giguere N, Barber JHM, Najarali Z, Khan MH, Thiele SL, Semmen MS et al (2017) Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant alpha-synuclein rat model of parkinsonism. Neurobiol Dis 106:133–146

    Article  CAS  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    Article  CAS  Google Scholar 

  • Huang XZ, Wen D, Zhang M, Xie Q, Ma L, Guan Y, Ren Y, Chen J, Hao CM (2014) Sirt1 activation ameliorates renal fibrosis by inhibiting the TGF-beta/Smad3 pathway. J Cell Biochem 115:996–1005

    Article  CAS  Google Scholar 

  • Jiang H, Kang SU, Zhang S, Karuppagounder S, Xu J, Lee YK, Kang BG, Lee Y, Zhang J, Pletnikova O et al (2016) Adult conditional knockout of PGC-1alpha leads to loss of dopamine neurons. eNeuro 3

  • Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13:2570–2580

    Article  CAS  Google Scholar 

  • Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912

    Article  CAS  Google Scholar 

  • Kim DH, Jung IH, Kim DH, Park SW (2019) Knockout of longevity gene Sirt1 in zebrafish leads to oxidative injury, chronic inflammation, and reduced life span. PLoS One 14:e0220581

  • Koronowski KB, Perez-Pinzon MA (2015) Sirt1 in cerebral ischemia. Brain Circ 1:69–78

    Article  Google Scholar 

  • Lee J, Sun C, Zhou Y, Lee J, Gokalp D, Herrema H, Park SW, Davis RJ, Ozcan U (2011) p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nature Medicine 17:1251–1260

    Article  CAS  Google Scholar 

  • Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A, Puigserver P (2006) GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab 3:429–438

    Article  CAS  Google Scholar 

  • Li B, Yang Y, Wang Y, Zhang J, Ding J, Liu X, Jin Y, Lian B, Ling Y, Sun C (2021) Acetylation of NDUFV1 induced by a newly synthesized HDAC6 inhibitor HGC rescues dopaminergic neuron loss in Parkinson models. iScience 24:102302

  • Liu L, Peritore C, Ginsberg J, Shih J, Arun S, Donmez G (2015) Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson’s disease. Behav Brain Res 281:215–221

    Article  CAS  Google Scholar 

  • Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB et al (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712–716

    Article  CAS  Google Scholar 

  • Mudo G, Makela J, Di Liberto V, Tselykh TV, Olivieri M, Piepponen P, Eriksson O, Malkia A, Bonomo A, Kairisalo M et al (2012) Transgenic expression and activation of PGC-1alpha protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol Life Sci 69:1153–1165

    Article  CAS  Google Scholar 

  • Nicholatos JW, Francisco AB, Bender CA, Yeh T, Lugay FJ, Salazar JE, Glorioso C, Libert S (2018) Nicotine promotes neuron survival and partially protects from Parkinson’s disease by suppressing SIRT6. Acta Neuropathol Commun 6:120

    Article  CAS  Google Scholar 

  • Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P et al (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907–918

    Article  CAS  Google Scholar 

  • Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317:516–519

    Article  CAS  Google Scholar 

  • Peng S, Wang C, Ma J, Jiang K, Jiang Y, Gu X, Sun C (2018) Achyranthes bidentata polypeptide protects dopaminergic neurons from apoptosis in Parkinson’s disease models both in vitro and in vivo. Br J Pharmacol 175:631–643

    Article  CAS  Google Scholar 

  • Piccinin E, Sardanelli AM, Seibel P, Moschetta A, Cocco T, Villani G (2021) PGC-1s in the spotlight with Parkinson’s disease. Int J Mol Sci 22

  • Quintas A, de Solis AJ, Diez-Guerra FJ, Carrascosa JM, Bogonez E (2012) Age-associated decrease of SIRT1 expression in rat hippocampus: prevention by late onset caloric restriction. Exp Gerontol 47:198–201

    Article  CAS  Google Scholar 

  • Rada P, Pardo V, Mobasher MA, Garcia-Martinez I, Ruiz L, Gonzalez-Rodriguez A, Sanchez-Ramos C, Muntane J, Alemany S, James LP et al (2018) SIRT1 controls acetaminophen hepatotoxicity by modulating inflammation and oxidative stress. Antioxid Redox Signal 28:1187–1208

    Article  CAS  Google Scholar 

  • Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118

    Article  CAS  Google Scholar 

  • Salimian N, Peymani M, Ghaedi K, Nasr Esfahani MH (2018) Modulation in miR-200a/SIRT1axis is associated with apoptosis in MPP(+)-induced SH-SY5Y cells. Gene 674:25–30

    Article  CAS  Google Scholar 

  • Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, Yamada KA, Imai S (2013) Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab 18:416–430

    Article  CAS  Google Scholar 

  • Sen N, Satija YK, Das S (2011) PGC-1alpha, a key modulator of p53, promotes cell survival upon metabolic stress. Mol Cell 44:621–634

    Article  CAS  Google Scholar 

  • Shi H, Deng HX, Gius D, Schumacker PT, Surmeier DJ, Ma YC (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915–1926

    Article  CAS  Google Scholar 

  • St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408

    Article  CAS  Google Scholar 

  • Sun C, Wang M, Liu X, Luo L, Li K, Zhang S, Wang Y, Yang Y, Ding F, Gu X (2014) PCAF improves glucose homeostasis by suppressing the gluconeogenic activity of PGC-1alpha. Cell Rep 9:2250–2262

    Article  CAS  Google Scholar 

  • Zakhary SM, Ayubcha D, Dileo JN, Jose R, Leheste JR, Horowitz JM, Torres G (2010) Distribution analysis of deacetylase SIRT1 in rodent and human nervous systems. Anat Rec (hoboken) 293:1024–1032

    Article  CAS  Google Scholar 

  • Zhang M, Deng YN, Zhang JY, Liu J, Li YB, Su H, Qu QM (2018) SIRT3 protects rotenone-induced injury in SH-SY5Y cells by promoting autophagy through the LKB1-AMPK-mTOR pathway. Aging Dis 9:273–286

    Article  Google Scholar 

  • Zhang Q, Liang XC (2019) Effects of mitochondrial dysfunction via AMPK/PGC-1 alpha signal pathway on pathogenic mechanism of diabetic peripheral neuropathy and the protective effects of chinese medicine. Chin J Integr Med 25:386–394

    Article  CAS  Google Scholar 

  • Zhang Z, Lowry SF, Guarente L, Haimovich B (2010) Roles of SIRT1 in the acute and restorative phases following induction of inflammation. J Biol Chem 285:41391–41401

    Article  CAS  Google Scholar 

  • Zheng Y, Dong L, Liu N, Luo X, He Z (2020) Mir-141-3p regulates apoptosis and mitochondrial membrane potential via targeting Sirtuin1 in a 1-methyl-4-phenylpyridinium in vitro model of Parkinson’s disease. Biomed Res Int 2020:7239895

    PubMed  PubMed Central  Google Scholar 

  • Zhu Y, Zhu X, Zhou Y, Zhang D (2021) Reduced serum SIRT1 levels in patients with Parkinson’s disease: a cross-sectional study in China. Neurol Sci 42:1835–1841

    Article  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81970747, 81770841) and the National Key Research and Development Program of China (Grant No. 2017YFA0701304).

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Author notes

  1. Yu Chen and Yuhui Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China

    Yu Chen

  2. Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, 19 Qixiu Road, Nantong, China

    Yuhui Jiang, Yinuo Yang & Cheng Sun

  3. Department of Nephrology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China

    Xinzhong Huang

  4. Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Institute of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, 20 Xishi Road, Nantong, China

    Cheng Sun

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  1. Yu Chen
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Correspondence to Cheng Sun.

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Chen, Y., Jiang, Y., Yang, Y. et al. SIRT1 Protects Dopaminergic Neurons in Parkinson’s Disease Models via PGC-1α-Mediated Mitochondrial Biogenesis. Neurotox Res 39, 1393–1404 (2021). https://doi.org/10.1007/s12640-021-00392-4

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