PGC-1α, Sirtuins and PARPs in Huntington’s Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All

  • Alejandro LloretEmail author
  • M. Flint Beal
Original Paper


In this review, we summarize the available published information on the neuroprotective effects of increasing nicotinamide adenine dinucleotide (NAD+) levels in Huntington’s disease models. We discuss the rationale of potential therapeutic benefit of administering nicotinamide riboside (NR), a safe and effective NAD+ precursor. We discuss the agonistic effect on the Sirtuin1-PGC-1α-PPAR pathway as well as Sirtuin 3, which converge in improving mitochondrial function, decreasing ROS production and ameliorating bioenergetics deficits. Also, we discuss the potential synergistic effect of increasing NAD+ combined with PARPs inhibitors, as a clinical therapeutic option not only in HD, but other neurodegenerative conditions.


Huntington’s disease NAD+ Nicotinamide Riboside Sirtruins PGC-1 alpha PARPs 



We are grateful for the support of NINDS grant 5R01NS086746-04.


  1. 1.
    MacDonald ME, Ambrose CM, Duyao MP et al (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 72:971–983CrossRefGoogle Scholar
  2. 2.
    Johri A, Calingasan NY, Hennessey T, Sharma A, Yang L, Wille E, Chandra A, Beal MF (2012) Pharamcologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet 21:1124–1137CrossRefPubMedGoogle Scholar
  3. 3.
    Podvin S, Reardon HT, Yin K, Mosier C, Hook V (2018) Multiple clinical features of Huntington’s disease correlate with mutant HTT gene CAG repeat lengths and neurodegeneration. J Neurol 266:551–564CrossRefPubMedGoogle Scholar
  4. 4.
    Pandey M, Rajamma U (2018) Huntington’s disease: the coming of age. J Genet 97(3):649–664CrossRefPubMedGoogle Scholar
  5. 5.
    Leung AKL (2017) PARPs. Curr Biol 27(23):R1256–R1258CrossRefPubMedGoogle Scholar
  6. 6.
    Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):829–839CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rowe GC, Arany Z (2014) Genetic models of PGC-1 and glucose metabolism and homeostasis. Rev Endocr Metab Disord 15(1):21–29CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C, PuigserverP Spiegelman B, Montminy M (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413(6852):179–183CrossRefPubMedGoogle Scholar
  9. 9.
    Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413(6852):131–138CrossRefPubMedGoogle Scholar
  10. 10.
    Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1(6):361–370CrossRefPubMedGoogle Scholar
  11. 11.
    Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A 100(12):7111–7116CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem 280(16):16456–16460CrossRefPubMedGoogle Scholar
  13. 13.
    Beeson CC, Beeson GC, Buff H, Eldridge J, Zhang A, Seth A, Demcheva M, Vournakis JN, Muise-Helmericks RC (2012) Integrin-dependent Akt1 activation regulates PGC-1 expression and fatty acid oxidation. Vasc Res 49(2):89–100CrossRefGoogle Scholar
  14. 14.
    Rodgers JT, Haas W, Gygi SP, Puigserver P (2010) Cdc2-like kinase 2 is an insulin-regulated suppressor of hepatic gluconeogenesis. Cell Metab 11(1):23–34CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhong N, Xu J (2008) Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation. Hum Mol Genet 17(21):3357–3367CrossRefPubMedGoogle Scholar
  16. 16.
    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(6):429–438CrossRefPubMedGoogle Scholar
  17. 17.
    Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC (2006) Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells. Proc Natl Acad Sci U S A 103(39):14379–14384CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Barger PM, Browning AC, Garner AN, Kelly DP (2001) p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem 276(48):44495–44501CrossRefPubMedGoogle Scholar
  19. 19.
    Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S, Mootha VK, Lowell BB, Spiegelman BM (2001) Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell 8(5):971–982CrossRefPubMedGoogle Scholar
  20. 20.
    Jäger S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104(29):12017–12022CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Che HV, Metzger S, Portal E, Deyle C, Riess O, Nguyen HP (2011) Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease. Mol Neurodegener 6(1):1CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L (2011) PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener 6(1):32CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Soyal SM, Felder TK, Auer S, Hahne P, Oberkofler H, Witting A, Paulmichl M, Landwehrmeyer GB, Weydt P, Patsch W, Network European Huntington Disease (2012) A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset. Hum Mol Genet 21(15):3461–3473CrossRefPubMedGoogle Scholar
  24. 24.
    Weydt P, Soyal SM, Landwehrmeyer GB, Patsch W, Network European Huntington Disease (2014) A single nucleotide polymorphism in the coding region of PGC-1α is a male-specific modifier of Huntington disease age-at-onset in a large European cohort. BMC Neurol 14:1CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jäger S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119(1):121–135CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005) PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3(4):e101CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Xiang Z, Valenza M, Cui L, Leoni V, Jeong HK, Brilli E, Zhang J, Peng Q, Duan W, Reeves SA, Cattaneo E, Krainc D (2011) Peroxisome-proliferator-activated receptor gamma coactivator 1 α contributes to dysmyelination in experimental models of Huntington’s disease. J Neurosci 31(26):9544–9553CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F, Cattaneo E, MacDonald ME (2000) Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Mol Genet 9:2799–2809CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127(1):59–69CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR (2006) Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4(5):349–362CrossRefPubMedGoogle Scholar
  31. 31.
    Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Chen H-SV, Tong G, Hayden MR, Lipton SA (2009) Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15:1407–1414CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, Cannella M, Sassone J, Ciammola A, Squitieri F, Beal MF (2009) Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet 18:3048–3065CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chaturvedi RK, Calingasan NY, Yang L, Hennessey T, Johri A, Beal MF (2010) Impairment of PGC- 1alpha expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington’s Disease following chronic energy deprivation. Hum Mol Genet 19:3190–3205CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB, Spiegelman BM (2003) PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 278(33):30843–30848CrossRefPubMedGoogle Scholar
  35. 35.
    Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormeir K, Smith K, Beal MF, Ferrante RJ (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet 19:3919–3935CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Martin E, Betuing S, Pagès C, Cambon K, Auregan G, Deglon N, Roze E, Caboche J (2011) Mitogen- and stress-activated protein kinase 1-induced neuroprotection in Huntington’s disease: role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet 20(12):2422–2434CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by thePGC-1 transcriptionalcoactivators. Cell 127:397–408CrossRefGoogle Scholar
  38. 38.
    Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E, La Spada AR (2012) PGC-1a rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 4:14297CrossRefGoogle Scholar
  39. 39.
    Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A 100:7111–7116CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009) PGC-1α and PGC-1β regulate mitochondrial density in neurons. J Biol Chem 284(32):21379–21385CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lee M, Liu T, Im W, Kim M (2016) Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington’s disease in vitro model. Eur J Neurosci 44(4):2114–2119CrossRefPubMedGoogle Scholar
  42. 42.
    Fujita Y, Yamashita T (2018) Sirtuins in neuroendocrine regulation and neurological diseases. Front Neurosci 12:778CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wang Y, He J, Liao M, Hu M, Li W, Ouyang H, Wang X, Ye T, Zhang Y, Ouyang L (2019) An overview of Sirtuins as potential therapeutic target: structure, function and modulators. Eur J Med Chem 161:48–77CrossRefPubMedGoogle Scholar
  44. 44.
    Pallas M, Pizarro JG, Gutierrez-Cuesta J, Crespo-Biel N, Alvira D, Tajes M, Yeste- Velasco M, Folch J, Canudas AM, Sureda FX, Ferrer I, Camins A (2008) Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. Neurosci 154:1388–1397CrossRefGoogle Scholar
  45. 45.
    Tulino R, Benjamin AC, Jolinon N, Smith DL, Chini EN, Carnemolla A, Bates GP (2016) SIRT1 activity is linked to its brain region-specific phosphorylation and is impaired in Huntington’s disease mice. PLoS ONE 11(1):e0145425CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, Yates JR 3rd, Bordone L, Guarente L, Krainc D (2011) Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 18:159–165CrossRefPubMedGoogle Scholar
  47. 47.
    Jiang M, Wang J, Fu J, Du L, Jeong H et al (2011) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18:153–158CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Zuccato C, Marullo M, Vitali B, Tarditi A, Mariotti C, Valenza M, Lahiri N, Wild EJ, Sassone J, Ciammola A, Bachoud-Lèvi AC, Tabrizi SJ, Di Donato S, Cattaneo E (2011) Brain-derived neurotrophic factor in patients with Huntington’s disease. PLoS ONE 6(8):e22966CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Cheng A, Wan R, Yang JL, Kamimura N, Son TG, Ouyang X, Luo Y, Okun E, Mattson MP (2012) Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nat Commun 3:1250CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Parker JA, Vasquez-Manrique RP, Tourette C, Farina F, Offner N, Mukhopadhyay A, Orfila AM, Darbois A, Menet S, Tissenbaum H, Neri C (2012) Integration of beta-catenin, sirtuin, and FOXO signaling protects from mutant huntingtin TOXICITY. J Neurosci 32:12630–12640CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lee M, Ban J-J, Chung J-Y, Im W, Kim M (2018) Amelioration of Huntington’s disease phenotypes by Beta-Lapachone is associated with increases in Sirt1 expression, CREB phosphorylation and PGC-1α deacetylation. PLoS ONE 13(5):e0195968CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Neri C (2005) Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37:349–350CrossRefPubMedGoogle Scholar
  53. 53.
    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 disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109–1122CrossRefPubMedGoogle Scholar
  54. 54.
    Ho DJ, Calingasan NY, Wille E, Dumont M, Beal MF (2010) Resveratrol protects against peripheral deficits in a mouse model of Huntington’s disease. Exp Neurol 225(1):74–84. CrossRefPubMedGoogle Scholar
  55. 55.
    Naia L, Rosenstock TR, Oliveira AM, Oliveira-Sousa SI, Caldeira GL, Carmo C, Laço MN, Hayden MR, Oliveira CR, Rego AC (2017) Comparative mitochondrial-based protective effects of resveratrol and nicotinamide in Huntington’s disease models. Mol Neurobiol 54(7):5385–5399CrossRefPubMedGoogle Scholar
  56. 56.
    Hathorn T, Snyder-Keller A, Messer A (2011) Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis 41(1):43–50CrossRefPubMedGoogle Scholar
  57. 57.
    Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB (1994) Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol 36(6):882–888CrossRefPubMedGoogle Scholar
  58. 58.
    Hwang ES, Song SB (2017) Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci 74:3347CrossRefPubMedGoogle Scholar
  59. 59.
    Jeong H, Then F, Melia TJ Jr, Mazzulli JR, Cui L, Savas JN, Voisine C, Paganetti P, Tanese N, Hart AC, Yamamoto A, Krainc D (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137(1):60–72CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS, Thompson LM, Marsh JL (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 17(23):3767–3775CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Sidhu A, Diwan V, Kaur H, Bhateja D, Singh CK, Sharma S, Padi SSV (2018) Nicotinamide reverses behavioral impairments and provides neuroprotection in 3-nitropropionic acid induced animal model of Huntington’s disease: implication of oxidative stress-poly(ADP-ribose) polymerase pathway. Metab Brain Dis 33(6):1911–1921CrossRefPubMedGoogle Scholar
  62. 62.
    Sasaki Y (2018) Metabolic aspects of neuronal degeneration: from a NAD+ point of view. Neurosci Res. CrossRefPubMedGoogle Scholar
  63. 63.
    Smith MR, Syed A, Lukacsovich T, Purcell J, Barbaro BA, Worthge SA, Wei SR, Pollio G, Magnoni L, Scali C, Massai L, Franceschini D, Camarri M, Gianfriddo M, Diodato E, Thomas R, Gokce O, Tabrizi SJ, Caricasole A, Landwehrmeyer B, Menalled L, Murphy C, Ramboz S, Luthi-Carter R, Westerberg G, Marsh JL (2014) A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet 23(11):2995–3007CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Westerberg G, Chiesa JA, Andersen CA, Diamanti D, Magnoni L, Pollio G, Darpo B, Zhou M (2015) Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1inhibitor selisistat in healthy volunteers. Br J Clin Pharmacol 79(3):477–491CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Reilmann R, Squitieri F, Priller J et al (2014) N02 Safety and tolerability of selisistat for the treatment of huntington’s disease: results from a randomised, double-blind, Placebo-controlled Phase Ii Trial. J Neurol Neurosurg Psychiatry 85:A102Google Scholar
  66. 66.
    Süssmuth SD, Haider S, Landwehrmeyer GB et al (2015) An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s disease. Br J Clin Pharmacol 79(3):465–476CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, Verdin EM, Kahn CR (2011) Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci U S A 108:14608–14613CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, Sinclair DA (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging 2:914–923CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130(6):1095–1107CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kim SH, Lu HF, Alano CC (2011) Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture. PLoS ONE 6:e14731CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Cimen H, Han MJ, Yang Y, Tong Q, Koc H (2010) Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49:304–311CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Qiu X, Brown K, Hirschey MD, Verdin E, Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3- mediated SOD2 activation. Cell Metab 12:662–667CrossRefPubMedGoogle Scholar
  73. 73.
    Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D (2010) Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 40:893–904CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Chen Y, Zhang J, Lin Y, Lei Q, Guan KL, Zhao S, Xiong Y (2011) Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep 12:534–541CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, Stancakova A, Goetzman E, Lam MM, Schwer B, Stevens RD, Muehlbauer MJ, Kakar S, Bass NM, Kuusisto J, Laakso M, Alt FW, Newgard CB, Farese RV Jr, Kahn CR, Verdin E (2011) SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44:177–190CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Chen T, Liu J, Li N, Wang S, Liu H, Li J, Zhang Y, Bu P (2015) Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD. PLoS ONE 10(3):e0118909CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Akie TE, Liu L, Nam M, Lei S, Cooper MP (2015) OXPHOS-mediated induction of NAD+ promotes complete oxidation of fatty acids and interdicts non-alcoholic fatty liver disease. PLoS ONE 10(5):e0125617CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Koentges C, Pfeil K, Schnick T, Wiese S, Dahlbock R, Cimolai MC, Meyer-Steenbuck M, Cenkerova K, Hoffmann MM, Jaeger C, Odening KE, Kammerer B, Hein L, Bode C, Bugger H (2015) SIRT3 deficiency impairs mitochondrial and contractile function in the heart. Basic Res Cardiol 110(4):36CrossRefPubMedGoogle Scholar
  79. 79.
    Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, Greco V, Maggiolini M, Feraco E, Mari V, Franceschi C, Passarino G, De Benedictis G (2005) A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 85(2):258–263CrossRefGoogle Scholar
  80. 80.
    Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA (2010) Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143:802–812CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Cheng A, Yang Y, Zhou Y, Maharana C, Lu D, Peng W, Liu Y, Wan R, Marosi K, Misiak M, Bohr VA, Mattson MP (2016) Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab 23(1):128–142CrossRefPubMedGoogle Scholar
  82. 82.
    Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13(10):4181–4192CrossRefPubMedGoogle Scholar
  83. 83.
    Brouillet E, Hantraye P (1995) Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates. Curr Opin Neurol 8(6):469–473CrossRefPubMedGoogle Scholar
  84. 84.
    Fu J, Jin J, Cichewicz RH, Hageman SA, Ellis TK, Xiang L, Peng Q, Jiang M, Arbez N, Hotaling K, Ross CA, Duan W (2012) trans-(-)-eViniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease. J Biol Chem 287:24460–24472CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Gibson BA, Kraus WL (2012) New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13(7):411–424CrossRefPubMedGoogle Scholar
  86. 86.
    Andrabi SA, Dawson TM, Dawson VL (2008) Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci 1147:233–241CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Galluzzi L, Kepp O, Kroemer G (2016) Mitochondrial regulation of cell death: a phylogenetically conserved control. Microb Cell 3(3):101–108CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Gibson GE, Starkov A, Blass JP, Ratan RR, Beal MF (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta 1801:122–134CrossRefGoogle Scholar
  89. 89.
    Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342(3):619–630CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Chandra A, Johri A, Beal MF (2014) Prospects for neuroprotective therapies in prodromal Huntington’s disease. Mov Disord 29(3):285–293CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Outeiro TF, Grammatopoulos TN, Altmann S, Amore A, Standaert DG, Hyman BT, Kazantsev AG (2007) Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+ -induced cytotoxicity in Parkinson’s disease in vitro models. Biochem Biophys Res Commun 357(3):596–602CrossRefPubMedGoogle Scholar
  92. 92.
    Lehmann S, Costa AC, Celardo I, Loh SH, Martins LM (2016) Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson’s disease. Cell Death Dis 7:e2166CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Kam TI, Mao X, Park H, Chou SC, Karuppagounder SS, Umanah GE, Yun SP, Brahmachari S, Panicker N, Chen R, Andrabi SA, Qi C, Poirier GG, Pletnikova O, Troncoso JC, Bekris LM, Leverenz JB, Pantelyat A, Ko HS, Rosenthal LS, Dawson TM, Dawson VL (2018) Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease. Science 362(6414):8407CrossRefGoogle Scholar
  94. 94.
    McGurk L, Mojsilovic-Petrovic J, Van Deerlin VM, Shorter J, Kalb RG, Lee VM, Trojanowski JQ, Lee EB, Bonini NM (2018) Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol Commun 6(1):84CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Martire S, Fuso A, Mosca L, Forte E, Correani V, Fontana M, Scarpa S, Maras B, d’Erme M (2016) Bioenergetic impairment in animal and cellular models of Alzheimer’s disease: PARP-1 inhibition rescues metabolic dysfunctions. J Alzheimers Dis 54(1):307–324CrossRefPubMedGoogle Scholar
  96. 96.
    Andreassen OA, Dedeoglu A, Friedlich A, Ferrante KL, Hughes D, Szabo C, Beal MF (2001) Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice. Exp Neurol 168(2):419–424CrossRefPubMedGoogle Scholar
  97. 97.
    Chen CM, Wu YR, Cheng ML, Liu JL, Lee YM, Lee PW, Soong BW, Chiu DT (2007) Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients. Biochem Biophys Res Commun 359(2):335–340CrossRefPubMedGoogle Scholar
  98. 98.
    Hands S, Sajjad MU, Newton MJ, Wyttenbach A (2011) In vitro and in vivo aggregation of a fragment of huntingtin protein directly causes free radical production. J Biol Chem 286:44512–44520CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Hung CL, Maiuri T, Bowie LE, Gotesman R, Son S, Falcone M, Giordano JV, Gillis T, Mattis V, Lau T, Kwan V, Wheeler V, Schertzer J, Singh K, Truant R (2018) A patient-derived cellular model for Huntington’s disease reveals phenotypes at clinically relevant CAG lengths. Mol Biol Cell 29(23):2809–2820CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Browne SE, Beal MF (2006) Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 8:2061–2073. CrossRefPubMedGoogle Scholar
  101. 101.
    Ayala-Peña S (2013) Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radic Biol Med 62:102–110CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Jędrak P, Mozolewski P, Węgrzyn G, Więckowski MR (2018) Mitochondrial alterations accompanied by oxidative stress conditions in skin fibroblasts of Huntington’s disease patients. Metab Brain Dis 33(6):2005–2017CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Askeland G, Dosoudilova Z, Rodinova M, Klempir J, Liskova I, Kuśnierczyk A, Bjørås M, Nesse G, Klungland A, Hansikova H, Eide L (2018) Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients. Sci Rep 8(1):9817CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Bogdanov MB, Andreassen OA, Dedeoglu A, Ferrante RJ, Beal MF (2001) Increased oxidative damage to DNA in a transgenic mouse model of Huntington’s disease. J Neurochem 79(6):1246–1249CrossRefPubMedGoogle Scholar
  105. 105.
    Askeland G, Rodinova M, Štufková H, Dosoudilova Z, Baxa M, Smatlikova P, Bohuslavova B, Klempir J, Nguyen TD, Kuśnierczyk A, Bjørås M, Klungland A, Hansikova H, Ellederova Z, Eide L (2018) A transgenic minipig model of Huntington’s disease shows early signs of behavioral and molecular pathologies. Dis Model Mech 1:2. CrossRefGoogle Scholar
  106. 106.
    Vis JC, Schipper E, de Boer-van Huizen RT, Verbeek MM, de Waal RM, Wesseling P, ten Donkelaar HJ, Kremer B (2005) Expression pattern of apoptosis-related markers in Huntington’s disease. Acta Neuropathol 109(3):321–328CrossRefPubMedGoogle Scholar
  107. 107.
    Cardinale A, Paldino E, Giampà C, Bernardi G, Fusco FR (2015) PARP-1 inhibition is neuroprotective in the R6/2 mouse model of Huntington’s disease. PLoS ONE 10(8):e0134482CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Paldino E, Cardinale A, D’Angelo V, Sauve I, Giampà C, Fusco FR (2017) Selective sparing of striatal interneurons after poly (ADP-ribose) polymerase 1 inhibition in the R6/2 mouse model of Huntington’s disease. Front Neuroanat 11:61CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Haigis MC, Guarente LP (2006) Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921CrossRefPubMedGoogle Scholar
  110. 110.
    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(7029):113–118CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS ONE 5(7):e11707CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Cantó C, Sauve AA, Bai P (2013) Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol Aspects Med 34(6):1168–1201CrossRefPubMedGoogle Scholar
  113. 113.
    Módis K, Gero D, Erdélyi K, Szoleczky P, DeWitt D, Szabo C (2012) Cellular bioenergetics is regulated by PARP1 under resting conditions and during oxidative stress. Biochem Pharmacol 83(5):633–643CrossRefPubMedGoogle Scholar
  114. 114.
    Oláh G, Szczesny B, Brunyánszki A, López-García IA, Gerö D, Radák Z, Szabo C (2015) Differentiation-associated downregulation of poly(ADP-ribose) polymerase-1 expression in myoblasts serves to increase their resistance to oxidative stress. PLoS ONE 10(7):e0134227CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Bai P, Cantó C, Brunyánszki A, Huber A, Szántó M, Cen Y, Yamamoto H, Houten SM, Kiss B, Oudart H, Gergely P, Menissier-de Murcia J, Schreiber V, Sauve AA, Auwerx J (2011) PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab 13(4):450–460CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Bai P, Cantó C, Oudart H, Brunyánszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH, Schoonjans K, Schreiber V, Sauve AA, Menissier-de Murcia J, Auwerx J (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13(4):461–468CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Wang S, Xing Z, Vosler PS, Yin H, Li W, Zhang F, Signore AP, Stetler RA, Gao Y, Chen J (2008) Cellular NAD replenishment confers marked neuroprotection against ischemic cell death role of enhanced DNA repair. Stroke 39:2587–2595CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Huang Q, Sun M, Li M et al (2018) Combination of NAD+ and NADPH offers greater neuroprotection in ischemic stroke models by relieving metabolic stress. Mol Neurobiol 55:6063CrossRefPubMedGoogle Scholar
  119. 119.
    Pittelli M, Felici R, Pitozzi V, Giovannelli L, Bigagli E, Cialdai F, Romano G, Moroni F, Chiarugi A (2011) Exogenous NAD and cytoprotection. Mol Pharmacol 80(6):1136–1146CrossRefPubMedGoogle Scholar
  120. 120.
    Rainer M, Kraxberger E, Haushofer M, Mucke HA, Jellinger KA (2000) No evidence for cognitive improvement from oral nicotinamide adenine dinucleotide (NADH) in dementia. J Neural Transm 107(12):1475–1481CrossRefPubMedGoogle Scholar
  121. 121.
    Swerdlow RH (1998) Is NADH effective in the treatment of Parkinson’s disease? Drugs Aging 13(4):263–268CrossRefPubMedGoogle Scholar
  122. 122.
    Birkmayer W, Birkmayer GJ, Vrecko K, Mlekusch W, Paletta B, Ott E (1989) The coenzyme nicotinamide adenine dinucleotide (NADH) improves the disability of parkinsonian patients. J Neural Transm Park Dis Dement Sect. 4:297–302CrossRefGoogle Scholar
  123. 123.
    Birkmayer W, Birkmayer JG, Vrecko K, Paletta B (1990) The clinical benefit of NADH as stimulator of endogenous L-dopa biosynthesis in parkinsonian patients. Adv Neurol 53:545–549PubMedGoogle Scholar
  124. 124.
    Birkmayer JG, Vrecko C, Volc D, Birkmayer W (1993) Nicotinamide adenine dinucleotide (NADH)–a new therapeutic approach to Parkinson’s disease. Comparison of oral and parenteral application. Acta Neurol Scand Suppl 146:32–35PubMedGoogle Scholar
  125. 125.
    Dizdar N, Kågedal B, Lindvall B (1994) Treatment of Parkinson’s disease with NADH. Acta Neurol Scand 90(5):345–347CrossRefPubMedGoogle Scholar
  126. 126.
    Alisky JM (2005) Niacin improved rigidity and bradykinesia in a Parkinson’s disease patient but also caused unacceptable nightmares and skin rash–a case report. Nutr Neurosci 8(5–6):327–329CrossRefPubMedGoogle Scholar
  127. 127.
    Phelan MJ, Mulnard RA, Gillen DL, Schreiber SS (2017) Phase II clinical trial of nicotinamide for the treatment of mild to moderate Alzheimer’s disease. J Geriatr Med Gerontol 3:021CrossRefGoogle Scholar
  128. 128.
    Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM (2008) Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 28(45):11500–11510CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Fricker RA, Green EL, Jenkins SI, Griffin SM (2018) The influence of nicotinamide on health and disease in the central nervous system. Int J Tryptophan Res 11:1178646918776658CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Gasperi V, Sibilano M, Savini I, Catani MV (2019) Niacin in the central nervous system: an update of biological aspects and clinical applications. Int J Mol Sci 20(4):E974CrossRefPubMedGoogle Scholar
  131. 131.
    Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C (2007) Nicotinamide rioside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 129:473–484CrossRefPubMedGoogle Scholar
  132. 132.
    Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D’Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352(6292):1436–1443CrossRefPubMedGoogle Scholar
  133. 133.
    Bieganowski P, Brenner C (2004) Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD þ in fungi and humans. Cell 117:495–502CrossRefPubMedGoogle Scholar
  134. 134.
    Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Cantó C (2016) NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun 7:13103CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Fletcher RS, Lavery G (2018) The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism. J Mol Endocrinol 2:4. CrossRefGoogle Scholar
  136. 136.
    Yang T, Chan NY, Sauve AA (2007) Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem 50(26):6458–6461CrossRefPubMedGoogle Scholar
  137. 137.
    Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J (2012) The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15:838–847CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Brown KD, Maqsood S, Huang JY, Pan Y, Harkcom W, Li W, Sauve A, Verdin E, Jaffrey SR (2014) Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab 20(6):1059–1068CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Schöndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, Giunta I, Schwarz LK, Di Napoli G, Panagiotakopoulou V, Nestel S, Keatinge M, Pruszak J, Bandmann O, Heimrich B, Gasser T, Whitworth AJ, Deleidi M (2018) The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson’s disease. Cell Rep 23(10):2976–2988CrossRefPubMedGoogle Scholar
  140. 140.
    Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM (2013) Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase; 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging 34:1581–1588CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, Zhang Y, Moritoh K, O’Connell JF, Baptiste BA, Stevnsner TV, Mattson MP, Bohr VA (2018) NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115(8):E1876–E1885CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Sykora P, Kanno S, Akbari M, Kulikowicz T, Baptiste BA, Leandro GS, Lu H, Tian J, May A, Becker KA, Croteau DL, Wilson DM 3rd, Sobol RW, Yasui A, Bohr VA (2017) DNA polymerase beta participates in mitochondrial DNA repair. Mol Cell Biol 37(16):e00237CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Prasad R, Çağlayan M, Dai DP, Nadalutti CA, Zhao ML, Gassman NR, Janoshazi AK, Stefanick DF, Horton JK, Krasich R, Longley MJ, Copeland WC, Griffith JD, Wilson SH (2017) DNA polymerase β: a missing link of the base excision repair machinery in mammalian mitochondria. DNA Repair 60:77–88CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Whitaker AM, Schaich MA, Smith MR, Flynn TS, Freudenthal BD (2017) Base excision repair of oxidative DNA damage: from mechanism to disease. Front Biosci 22:1493–1522CrossRefGoogle Scholar
  145. 145.
    Weissman L, Jo DG, Sørensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP, Bohr VA (2007) Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res 35(16):5545–5555CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Misiak M, Vergara Greeno R, Baptiste BA, Sykora P, Liu D, Cordonnier S, Fang EF, Croteau DL, Mattson MP, Bohr VA (2017) DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer’s disease. Aging Cell 16(1):162–172CrossRefPubMedGoogle Scholar
  147. 147.
    Sykora P, Misiak M, Wang Y, Ghosh S, Leandro GS, Liu D, Tian J, Baptiste BA, Cong WN, Brenerman BM, Fang E, Becker KG, Hamilton RJ, Chigurupati S, Zhang Y, Egan JM, Croteau DL, Wilson DM, Mattson MP, Bohr VA (2015) DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res 43(2):943–959CrossRefPubMedGoogle Scholar
  148. 148.
    DiGiovanni LF, Mocle AJ, Xia J, Truant R (2016) Huntingtin N17 domain is a reactive oxygen species sensor regulating huntingtin phosphorylation and localization. Hum Mol Genet 25(18):3937–3945CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Gu X, Greiner ER, Mishra R, Kodali R, Osmand A, Finkbeiner S, Steffan JS, Thompson LM, Wetzel R, Yang XW (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64(6):828–840CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Maiuri T, Mocle AJ, Hung CL, Xia J, van Roon-Mom WM, Truant R (2017) Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. Hum Mol Genet 26(2):395–406PubMedGoogle Scholar
  151. 151.
    Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268(5218):1749–1753CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA (2016) NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24(4):566–581CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Vijayvargia R, Epand R, Leitner A, Jung TY, Shin B, Jung R, Lloret A, Singh Atwal R, Lee H, Lee JM, Aebersold R, Hebert H, Song JJ, Seong IS (2016) Huntingtin’s spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function. Elife 5:e11184CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Rui YN, Xu Z, Patel B, Chen Z, Chen D, Tito A, David G, Sun Y, Stimming EF, Bellen HJ, Cuervo AM, Zhang S (2015) Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol 17(3):262–275CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    MacDonald ME, Barnes G, Srinidhi J, Duyao MP, Ambrose CM, Myers RH, Gray J, Conneally PM, Young A, Penney J et al (1993) Gametic but not somatic instability of CAG repeat length in Huntington’s disease. J Med Genet 30(12):982–986CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Goula A-V, Berquist BR, Wilson DM III, Wheeler VC, Trottier Y, Merienne K (2009) Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington’s disease transgenic mice. PLoS Genet 5(12):e1000749CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Dragileva E, Hendricks A, Teed A, Gillis T, Lopez ET, Friedberg EC, Kucherlapati R, Edelmann W, Lunetta KL, MacDonald ME, Wheeler VC (2009) Intergenerational and striatal CAG repeat instability in Huntington’s disease knock-in mice involve different DNA repair genes. Neurobiol Dis 33(1):37–47CrossRefPubMedGoogle Scholar
  158. 158.
    Swami M, Hendricks AE, Gillis T, Massood T, Mysore J, Myers RH, Wheeler VC (2009) Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum Mol Genet 18(16):3039–3047CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447(7143):447–452CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Lopez-Castel A, Tomkinson AE, Pearson CE (2009) CTG/CAG repeat instability is modulated by the levels of human DNA ligase I and its interaction with PCNA: a distinction between replication and slipped-DNA repair. J Biol Chem 284:26631–26645CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Goula AV, Pearson CE, Della Maria J, Trottier Y, Tomkinson AE, Wilson DM, Merienne K (2012) The nucleotide sequence, DNA damage location, and protein stoichiometry influence the base excision repair outcome at CAG/CTG repeats. Biochemistry 51(18):3919–3932CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Liu Y, Prasad R, Beard WA, Hou EW, Horton JK, McMurray CT, Wilson SH (2009) Coordination between polymerase beta and FEN1 can modulate CAG repeat expansion. J Biol Chem 284(41):28352–28366CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Hoch NC, Hanzlikova H, Rulten SL, Tétreault M, Komulainen E, Ju L, Hornyak P, Zeng Z, Gittens W, Rey SA, Staras K, Mancini GM, McKinnon PJ, Wang ZQ, Wagner JD, Yoon G, Caldecott KW, Care4Rare Canada Consortium (2017) XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541(7635):87–91CrossRefPubMedGoogle Scholar
  164. 164.
    Vaur P, Brugg B, Mericskay M, Li Z, Schmidt MS, Vivien D, Orset C, Jacotot E, Brenner C, Duplus E (2017) Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J 31(12):5440–5452CrossRefPubMedGoogle Scholar
  165. 165.
    Harlan BA, Pehar M, Sharma DR, Beeson G, Beeson CC, Vargas MR (2016) Enhancing NAD+ salvage pathway reverts the toxicity of primary astrocytes expressing amyotrophic lateral sclerosis-linked mutant superoxide dismutase 1 (SOD1). J Biol Chem 291(20):10836–10846CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Conze DB, Crespo-Barreto J, Kruger CL (2016) Safety assessment of nicotinamide riboside, a form of vitamin B3. Hum Exp Toxicol 35(11):1149–1160CrossRefPubMedGoogle Scholar
  167. 167.
    Dellinger RW, Santos SR, Morris M, Evans M, Alminana D, Guarente L, Marcotulli E (2017) Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis 3:17CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR (2018) Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun 9(1):1286CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Feil Family Brain and Mind Research InstituteWeill Cornell Medical CollegeNew YorkUSA
  2. 2.NeuCyte PharmaceuticalsSan CarlosUSA

Personalised recommendations