Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a Common Strategy for Neurodegenerative Diseases

Literature Cited

1. 1. 

   Feigin VL, Vos T, Nichols E, Owolabi MO, Carroll WM et al. 2020. The global burden of neurological disorders: translating evidence into policy. Lancet Neurol 19:255–65
   [Google Scholar]
2. 2. 

   Liu P, Kerins MJ, Tian W, Neupane D, Zhang DD, Ooi A. 2019. Differential and overlapping targets of the transcriptional regulators NRF1, NRF2, and NRF3 in human cells. J. Biol. Chem. 294:18131–49
   [Google Scholar]
3. 3. 

   Bai F, Hong D, Lu Y, Liu H, Xu C, Yao X. 2019. Prediction of the antioxidant response elements’ response of compound by deep learning. Front. Chem. 7:385
   [Google Scholar]
4. 4. 

   Baird L, Yamamoto M. 2020. The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol. Cell. Biol. 40:13e00099-20
   [Google Scholar]
5. 5. 

   Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP et al. 2019. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18:295–317
   [Google Scholar]
6. 6. 

   Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG, Cotte A et al. 2012. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol. Cell. Biol. 32:3486–99
   [Google Scholar]
7. 7. 

   Cuadrado A. 2015. Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP. Free Radic. Biol. Med. 88:147–57
   [Google Scholar]
8. 8. 

   Mines MA, Beurel E, Jope RS 2011. Regulation of cell survival mechanisms in Alzheimer's disease by glycogen synthase kinase-3. Int. J. Alzheimer's Dis. 2011.861072
   [Google Scholar]
9. 9. 

   Li DW, Liu ZQ, Chen W, Yao M, Li GR 2014. Association of glycogen synthase kinase-3β with Parkinson's disease. Mol. Med. Rep. 9:2043–50
   [Google Scholar]
10. 10. 

    Numazawa S, Ishikawa M, Yoshida A, Tanaka S, Yoshida T. 2003. Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. Am. J. Physiol. Cell Physiol. 285:C334–42
    [Google Scholar]
11. 11. 

    Zeng H, Wang L, Zhang J, Pan T, Yu Y et al. 2021. Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: therapeutic efficacy of dihydrotanshinone-I. Acta Pharm. Sin. B 11:71–88
    [Google Scholar]
12. 12. 

    Sun Z, Huang Z, Zhang DD. 2009. Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLOS ONE 4:e6588
    [Google Scholar]
13. 13. 

    Matzinger M, Fischhuber K, Poloske D, Mechtler K, Heiss EH. 2020. AMPK leads to phosphorylation of the transcription factor Nrf2, tuning transactivation of selected target genes. Redox Biol 29:101393
    [Google Scholar]
14. 14. 

    Jimenez-Blasco D, Santofimia-Castano P, Gonzalez A, Almeida A, Bolanos JP. 2015. Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5-Nrf2 pathway. Cell Death Differ 22:1877–89
    [Google Scholar]
15. 15. 

    Paladino S, Conte A, Caggiano R, Pierantoni GM, Faraonio R. 2018. Nrf2 pathway in age-related neurological disorders: insights into microRNAs. Cell Physiol. Biochem. 47:1951–76
    [Google Scholar]
16. 16. 

    Silva-Palacios A, Ostolga-Chavarria M, Zazueta C, Konigsberg M. 2018. Nrf2: molecular and epigenetic regulation during aging. Ageing Res. Rev. 47:31–40
    [Google Scholar]
17. 17. 

    Honkura Y, Matsuo H, Murakami S, Sakiyama M, Mizutari K et al. 2016. NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea. Sci. Rep. 6:19329
    [Google Scholar]
18. 18. 

    Oishi T, Matsumaru D, Ota N, Kitamura H, Zhang T et al. 2020. Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss. NPJ Aging Mech. Dis. 6:14
    [Google Scholar]
19. 19. 

    Martin-de-Saavedra MD, Budni J, Cunha MP, Gomez-Rangel V, Lorrio S et al. 2013. Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. Psychoneuroendocrinology 38:2010–22
    [Google Scholar]
20. 20. 

    Gergues MM, Moiseyenko A, Saad SZ, Kong AN, Wagner GC. 2018. Nrf2 deletion results in impaired performance in memory tasks and hyperactivity in mature and aged mice. Brain Res 1701:103–11
    [Google Scholar]
21. 21. 

    Zweig JA, Caruso M, Brandes MS, Gray NE. 2020. Loss of NRF2 leads to impaired mitochondrial function, decreased synaptic density and exacerbated age-related cognitive deficits. Exp. Gerontol. 131:110767
    [Google Scholar]
22. 22. 

    Rojo AI, Pajares M, Rada P, Nunez A, Nevado-Holgado AJ et al. 2017. NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology. Redox Biol 13:444–51
    [Google Scholar]
23. 23. 

    Hubbs AF, Benkovic SA, Miller DB, O'Callaghan JP, Battelli L et al. 2007. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am. J. Pathol. 170:2068–76
    [Google Scholar]
24. 24. 

    Kubben N, Zhang W, Wang L, Voss TC, Yang J et al. 2016. Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361–74
    [Google Scholar]
25. 25. 

    Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, Buffenstein R 2015. Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. PNAS 112:3722–27
    [Google Scholar]
26. 26. 

    Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P et al. 2011. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am. J. Physiol. Heart Circ. Physiol. 301:H363–72
    [Google Scholar]
27. 27. 

    Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M et al. 2011. Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-κB activation in the nonhuman primate Macaca mulatta. J. Gerontol. A Biol. Sci. Med. Sci. 66:866–75
    [Google Scholar]
28. 28. 

    Kuosmanen SM, Sihvola V, Kansanen E, Kaikkonen MU, Levonen AL. 2018. MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells. Redox Biol 18:77–83
    [Google Scholar]
29. 29. 

    Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD. 2019. Redox regulation by NRF2 in aging and disease. Free Radic. Biol. Med. 134:702–7
    [Google Scholar]
30. 30. 

    Babcock KR, Page JS, Fallon JR, Webb AE 2021. Adult hippocampal neurogenesis in aging and Alzheimer's disease. Stem Cell Rep 16:681–93
    [Google Scholar]
31. 31. 

    Kahroba H, Ramezani B, Maadi H, Sadeghi MR, Jaberie H, Ramezani F 2021. The role of Nrf2 in neural stem/progenitors cells: from maintaining stemness and self-renewal to promoting differentiation capability and facilitating therapeutic application in neurodegenerative disease. Ageing Res. Rev. 65:101211
    [Google Scholar]
32. 32. 

    Ray S, Corenblum MJ, Anandhan A, Reed A, Ortiz FO et al. 2018. A role for Nrf2 expression in defining the aging of hippocampal neural stem cells. Cell Transplant. 27:589–606
    [Google Scholar]
33. 33. 

    Bell KFS, Al-Mubarak B, Martel MA, McKay S, Wheelan N et al. 2015. Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2. Nat. Commun. 6:7066
    [Google Scholar]
34. 34. 

    Obernier K, Alvarez-Buylla A. 2019. Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain. Development 146:4dev156059
    [Google Scholar]
35. 35. 

    Robledinos-Anton N, Rojo AI, Ferreiro E, Nunez A, Krause KH et al. 2017. Transcription factor NRF2 controls the fate of neural stem cells in the subgranular zone of the hippocampus. Redox Biol 13:393–401
    [Google Scholar]
36. 36. 

    Karkkainen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A et al. 2014. Nrf2 regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells 32:1904–16
    [Google Scholar]
37. 37. 

    Kraft AD, Resch JM, Johnson DA, Johnson JA 2007. Activation of the Nrf2-ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1. Exp. Neurol. 207:107–17
    [Google Scholar]
38. 38. 

    Zhang H, Liu H, Davies KJ, Sioutas C, Finch CE et al. 2012. Nrf2-regulated phase II enzymes are induced by chronic ambient nanoparticle exposure in young mice with age-related impairments. Free Radic. Biol. Med. 52:2038–46
    [Google Scholar]
39. 39. 

    Raina AK, Templeton DJ, Deak JC, Perry G, Smith MA 1999. Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer's disease. Redox Rep 4:23–27
    [Google Scholar]
40. 40. 

    Wang Y, Santa-Cruz K, DeCarli C, Johnson JA 2000. NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer's disease. Neurobiol. Aging 21:525–31
    [Google Scholar]
41. 41. 

    SantaCruz KS, Yazlovitskaya E, Collins J, Johnson J, DeCarli C 2004. Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer's disease. Neurobiol. Aging 25:63–69
    [Google Scholar]
42. 42. 

    Schipper HM, Cisse S, Stopa EG 1995. Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann. Neurol. 37:758–68
    [Google Scholar]
43. 43. 

    Aksenov MY, Markesbery WR. 2001. Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer's disease. Neurosci. Lett. 302:141–45
    [Google Scholar]
44. 44. 

    Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP et al. 2007. Expression of Nrf2 in neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 66:75–85
    [Google Scholar]
45. 45. 

    Lovell MA, Xie C, Markesbery WR. 1998. Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease. Neurology 51:1562–66
    [Google Scholar]
46. 46. 

    Lastres-Becker I, Innamorato NG, Jaworski T, Rabano A, Kugler S et al. 2014. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain 137:78–91
    [Google Scholar]
47. 47. 

    Pajares M, Jimenez-Moreno N, Garcia-Yague AJ, Escoll M, de Ceballos ML et al. 2016. Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12:1902–16
    [Google Scholar]
48. 48. 

    Cuadrado A, Kugler S, Lastres-Becker I. 2018. Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biol 14:522–34
    [Google Scholar]
49. 49. 

    Moi P, Chan K, Asunis I, Cao A, Kan YW 1994. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. PNAS 91:9926–30
    [Google Scholar]
50. 50. 

    Lee JM, Calkins MJ, Chan K, Kan YW, Johnson JA 2003. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J. Biol. Chem. 278:12029–38
    [Google Scholar]
51. 51. 

    Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA et al. 2009. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. PNAS 106:2933–38
    [Google Scholar]
52. 52. 

    Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T et al. 2012. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22:66–79
    [Google Scholar]
53. 53. 

    Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J et al. 2013. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J. Clin. Investig. 123:2921–34
    [Google Scholar]
54. 54. 

    Kirby J, Halligan E, Baptista MJ, Allen S, Heath PR et al. 2005. Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS. Brain 128:1686–706
    [Google Scholar]
55. 55. 

    Mashima K, Takahashi S, Minami K, Izawa Y, Abe T et al. 2018. Neuroprotective role of astroglia in Parkinson disease by reducing oxidative stress through dopamine-induced activation of pentose-phosphate pathway. ASN Neuro 10:1759091418775562
    [Google Scholar]
56. 56. 

    Cuadrado A, Moreno-Murciano P, Pedraza-Chaverri J. 2009. The transcription factor Nrf2 as a new therapeutic target in Parkinson's disease. Expert Opin. Ther. Targets 13:319–29
    [Google Scholar]
57. 57. 

    Zafar KS, Inayat-Hussain SH, Siegel D, Bao A, Shieh B, Ross D 2006. Overexpression of NQO1 protects human SK-N-MC neuroblastoma cells against dopamine-induced cell death. Toxicol. Lett. 166:261–67
    [Google Scholar]
58. 58. 

    Parga JA, Rodriguez-Perez AI, Garcia-Garrote M, Rodriguez-Pallares J, Labandeira-Garcia JL. 2018. Angiotensin II induces oxidative stress and upregulates neuroprotective signaling from the NRF2 and KLF9 pathway in dopaminergic cells.. Free Radic. Biol. Med. 129:394–406
    [Google Scholar]
59. 59. 

    Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP 2009. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat. Cell Biol. 11:747–52
    [Google Scholar]
60. 60. 

    Lopez-Fabuel I, Le Douce J, Logan A, James AM, Bonvento G et al. 2016. Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. PNAS 113:13063–68
    [Google Scholar]
61. 61. 

    Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M et al. 2007. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55:1251–62
    [Google Scholar]
62. 62. 

    Gegg ME, Beltran B, Salas-Pino S, Bolanos JP, Clark JB et al. 2003. Differential effect of nitric oxide on glutathione metabolism and mitochondrial function in astrocytes and neurones: implications for neuroprotection/neurodegeneration?. J. Neurochem. 86:228–37
    [Google Scholar]
63. 63. 

    Bolanos JP, Delgado-Esteban M, Herrero-Mendez A, Fernandez-Fernandez S, Almeida A. 2008. Regulation of glycolysis and pentose-phosphate pathway by nitric oxide: impact on neuronal survival. Biochim. Biophys. Acta 1777:789–93
    [Google Scholar]
64. 64. 

    Baxter PS, Hardingham GE. 2016. Adaptive regulation of the brain's antioxidant defences by neurons and astrocytes. Free Radic. Biol. Med. 100:147–52
    [Google Scholar]
65. 65. 

    Belov Kirdajova D, Kriska J, Tureckova J, Anderova M 2020. Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front. Cell Neurosci. 14:51
    [Google Scholar]
66. 66. 

    Armada-Moreira A, Gomes JI, Pina CC, Savchak OK, Goncalves-Ribeiro J et al. 2020. Going the extra (synaptic) mile: excitotoxicity as the road toward neurodegenerative diseases. Front. Cell Neurosci. 14:90
    [Google Scholar]
67. 67. 

    Brekke E, Berger HR, Wideroe M, Sonnewald U, Morken TS. 2017. Glucose and intermediary metabolism and astrocyte-neuron interactions following neonatal hypoxia-ischemia in rat. Neurochem. Res. 42:115–32
    [Google Scholar]
68. 68. 

    Shahraz A, Wissfeld J, Ginolhac A, Mathews M, Sinkkonen L, Neumann H. 2021. Phagocytosis-related NADPH oxidase 2 subunit gp91phox contributes to neurodegeneration after repeated systemic challenge with lipopolysaccharides. Glia 69:137–50
    [Google Scholar]
69. 69. 

    Zhang C, Wang H, Liang W, Yang Y, Cong C et al. 2021. Diphenyl diselenide protects motor neurons through inhibition of microglia-mediated inflammatory injury in amyotrophic lateral sclerosis. Pharmacol. Res. 165:105457
    [Google Scholar]
70. 70. 

    Devanney NA, Stewart AN, Gensel JC. 2020. Microglia and macrophage metabolism in CNS injury and disease: the role of immunometabolism in neurodegeneration and neurotrauma. Exp. Neurol. 329:113310
    [Google Scholar]
71. 71. 

    Cuadrado A, Martin-Moldes Z, Ye J, Lastres-Becker I 2014. Transcription factors NRF2 and NF-κB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J. Biol. Chem. 289:15244–58
    [Google Scholar]
72. 72. 

    Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D et al. 2018. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556:113–17
    [Google Scholar]
73. 73. 

    Zhang S, Jiao Y, Li C, Liang X, Jia H et al. 2020. Dimethyl itaconate alleviates the inflammatory responses of macrophages in sepsis. Inflammation 44:549–57
    [Google Scholar]
74. 74. 

    Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E et al. 2018. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature 556:501–4
    [Google Scholar]
75. 75. 

    Kuo PC, Weng WT, Scofield BA, Paraiso HC, Brown DA et al. 2020. Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis. J. Neuroinflamm. 17:138
    [Google Scholar]
76. 76. 

    Joseph E, Villalobos-Acosta DMA, Torres-Ramos MA, Farfan-Garcia ED, Gomez-Lopez M et al. 2020. Neuroprotective effects of apocynin and galantamine during the chronic administration of scopolamine in an Alzheimer's disease model. J. Mol. Neurosci. 70:180–93
    [Google Scholar]
77. 77. 

    Mitchell S, Vargas J, Hoffmann A. 2016. Signaling via the NFκB system. Wiley Interdiscip. Rev. Syst. Biol. Med. 8:227–41
    [Google Scholar]
78. 78. 

    Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M et al. 2006. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Investig. 116:984–95
    [Google Scholar]
79. 79. 

    Lee Y, Shin DH, Kim JH, Hong S, Choi D et al. 2010. Caffeic acid phenethyl ester-mediated Nrf2 activation and IκB kinase inhibition are involved in NFκB inhibitory effect: structural analysis for NFκB inhibition. Eur. J. Pharmacol. 643:21–28
    [Google Scholar]
80. 80. 

    Brune B, Dehne N, Grossmann N, Jung M, Namgaladze D et al. 2013. Redox control of inflammation in macrophages. Antioxid. Redox Signal. 19:595–637
    [Google Scholar]
81. 81. 

    Todorovic M, Newman JR, Shan J, Bentley S, Wood SA et al. 2015. Comprehensive assessment of genetic sequence variants in the antioxidant ‘master regulator’ NRF2 in idiopathic Parkinson's disease. PLOS ONE 10:e0128030
    [Google Scholar]
82. 82. 

    Bergstrom P, von Otter M, Nilsson S, Nilsson AC, Nilsson M et al. 2014. Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 15:130–37
    [Google Scholar]
83. 83. 

    von Otter M, Landgren S, Nilsson S, Zetterberg M, Celojevic D et al. 2010. Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract. Mech. Ageing Dev. 131:105–10
    [Google Scholar]
84. 84. 

    Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M et al. 2016. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7:11624
    [Google Scholar]
85. 85. 

    Ishii T, Mann GE. 2014. Redox status in mammalian cells and stem cells during culture in vitro: critical roles of Nrf2 and cystine transporter activity in the maintenance of redox balance. Redox Biol 2:786–94
    [Google Scholar]
86. 86. 

    Harvey CJ, Thimmulappa RK, Sethi S, Kong X, Yarmus L et al. 2011. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci. Transl. Med. 3:78ra32
    [Google Scholar]
87. 87. 

    Saddawi-Konefka R, Seelige R, Gross ET, Levy E, Searles SC et al. 2016. Nrf2 induces IL-17D to mediate tumor and virus surveillance. Cell Rep 16:2348–58
    [Google Scholar]
88. 88. 

    Liu GH, Qu J, Shen X. 2008. NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim. Biophys. Acta 1783:713–27
    [Google Scholar]
89. 89. 

    Rushworth SA, Zaitseva L, Murray MY, Shah NM, Bowles KM, MacEwan DJ. 2012. The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. Blood 120:5188–98
    [Google Scholar]
90. 90. 

    Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA. 2010. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol. Sci. 114:237–46
    [Google Scholar]
91. 91. 

    Buendia I, Michalska P, Navarro E, Gameiro I, Egea J, Leon R 2016. Nrf2-ARE pathway: an emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol. Ther. 157:84–104
    [Google Scholar]
92. 92. 

    Licht-Mayer S, Wimmer I, Traffehn S, Metz I, Bruck W et al. 2015. Cell type-specific Nrf2 expression in multiple sclerosis lesions. Acta Neuropathol 130:263–77
    [Google Scholar]
93. 93. 

    van Horssen J, Drexhage JA, Flor T, Gerritsen W, van der Valk P, de Vries HE. 2010. Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic. Biol. Med. 49:1283–89
    [Google Scholar]
94. 94. 

    Tzima S, Victoratos P, Kranidioti K, Alexiou M, Kollias G. 2009. Myeloid heme oxygenase-1 regulates innate immunity and autoimmunity by modulating IFN-β production. J. Exp. Med. 206:1167–79
    [Google Scholar]
95. 95. 

    Fagone P, Patti F, Mangano K, Mammana S, Coco M et al. 2013. Heme oxygenase-1 expression in peripheral blood mononuclear cells correlates with disease activity in multiple sclerosis. J. Neuroimmunol. 261:82–86
    [Google Scholar]
96. 96. 

    Hashimoto M, Rockenstein E, Crews L, Masliah E. 2003. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromol. Med. 4:21–36
    [Google Scholar]
97. 97. 

    Pajares M, Cuadrado A, Rojo AI 2017. Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases. Redox Biol 11:543–53
    [Google Scholar]
98. 98. 

    Rubinsztein DC. 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780–86
    [Google Scholar]
99. 99. 

    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–84
    [Google Scholar]
100. 100. 

     Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T et al. 2010. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30:3275–85
     [Google Scholar]
101. 101. 

     Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA et al. 2010. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285:22576–91
     [Google Scholar]
102. 102. 

     Fan W, Tang Z, Chen D, Moughon D, Ding X et al. 2010. Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. Autophagy 6:614–21
     [Google Scholar]
103. 103. 

     Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A et al. 2010. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12:213–23
     [Google Scholar]
104. 104. 

     Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J et al. 2013. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 51:618–31
     [Google Scholar]
105. 105. 

     Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV 2014. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 5:3496
     [Google Scholar]
106. 106. 

     Joshi G, Gan KA, Johnson DA, Johnson JA 2015. Increased Alzheimer's disease-like pathology in the APP/PS1δE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol. Aging 36:664–79
     [Google Scholar]
107. 107. 

     Mou Y, Wen S, Li YX, Gao XX, Zhang X, Jiang ZY. 2020. Recent progress in Keap1-Nrf2 protein-protein interaction inhibitors. Eur. J. Med. Chem. 202:112532
     [Google Scholar]
108. 108. 

     Brandes MS, Gray NE. 2020. NRF2 as a therapeutic target in neurodegenerative diseases. ASN Neuro 12:1759091419899782
     [Google Scholar]
109. 109. 

     Dinkova-Kostova AT, Kostov RV, Kazantsev AG 2018. The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS J 285:3576–90
     [Google Scholar]
110. 110. 

     Lastra D, Fernandez-Gines R, Manda G, Cuadrado A 2021. Perspectives on the clinical development of NRF2-targeting drugs. Handb. Exp. Pharmacol. 264:93–141
     [Google Scholar]
111. 111. 

     Robledinos-Anton N, Fernandez-Gines R, Manda G, Cuadrado A 2019. Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid. Med. Cell Longev. 2019.9372182
     [Google Scholar]
112. 112. 

     Cuadrado A, Manda G, Hassan A, Alcaraz MJ, Barbas C et al. 2018. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol. Rev. 70:348–83
     [Google Scholar]
113. 113. 

     Baird L, Swift S, Lleres D, Dinkova-Kostova AT. 2014. Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol. Adv. 32:1133–44
     [Google Scholar]
114. 114. 

     Albrecht P, Bouchachia I, Goebels N, Henke N, Hofstetter HH et al. 2012. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J. Neuroinflamm. 9:163
     [Google Scholar]
115. 115. 

     Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R et al. 2011. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–92
     [Google Scholar]
116. 116. 

     Lee DH, Gold R, Linker RA. 2012. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int. J. Mol. Sci. 13:11783–803
     [Google Scholar]
117. 117. 

     Benardais K, Pul R, Singh V, Skripuletz T, Lee DH et al. 2013. Effects of fumaric acid esters on blood-brain barrier tight junction proteins. Neurosci. Lett. 555:165–70
     [Google Scholar]
118. 118. 

     Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A et al. 2016. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. PNAS 113:4777–82
     [Google Scholar]
119. 119. 

     Chen H, Assmann JC, Krenz A, Rahman M, Grimm M et al. 2014. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J. Clin. Investig. 124:2188–92
     [Google Scholar]
120. 120. 

     Scuderi SA, Ardizzone A, Paterniti I, Esposito E, Campolo M. 2020. Antioxidant and anti-inflammatory effect of Nrf2 inducer dimethyl fumarate in neurodegenerative diseases. Antioxidants 9:7630
     [Google Scholar]
121. 121. 

     Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X et al. 2005. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. PNAS 102:4584–89
     [Google Scholar]
122. 122. 

     Lynch DR, Johnson J. 2021. Omaveloxolone: potential new agent for Friedreich ataxia. Neurodegener. Dis. Manag. 11:291–98
     [Google Scholar]
123. 123. 

     Abeti R, Baccaro A, Esteras N, Giunti P. 2018. Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich's ataxia models. Front. Cell Neurosci. 12:188
     [Google Scholar]
124. 124. 

     Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M et al. 2021. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann. Neurol. 89:212–25
     [Google Scholar]
125. 125. 

     Schepici G, Bramanti P, Mazzon E. 2020. Efficacy of sulforaphane in neurodegenerative diseases. Int. J. Mol. Sci. 21:8637
     [Google Scholar]
126. 126. 

     Townsend BE, Johnson RW 2016. Sulforaphane induces Nrf2 target genes and attenuates inflammatory gene expression in microglia from brain of young adult and aged mice. Exp. Gerontol. 73:42–48
     [Google Scholar]
127. 127. 

     Quinti L, Casale M, Moniot S, Pais TF, Van Kanegan MJ et al. 2016. SIRT2- and NRF2-targeting thiazole-containing compound with therapeutic activity in Huntington's disease models. Cell Chem. Biol. 23:849–61
     [Google Scholar]
128. 128. 

     Jazwa A, Rojo AI, Innamorato NG, Hesse M, Fernandez-Ruiz J, Cuadrado A. 2011. Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid. Redox Signal. 14:2347–60
     [Google Scholar]
129. 129. 

     Morroni F, Tarozzi A, Sita G, Bolondi C, Zolezzi Moraga JM et al. 2013. Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson's disease. Neurotoxicology 36:63–71
     [Google Scholar]
130. 130. 

     Zhou Q, Chen B, Wang X, Wu L, Yang Y et al. 2016. Sulforaphane protects against rotenone-induced neurotoxicity in vivo: involvement of the mTOR, Nrf2, and autophagy pathways. Sci. Rep. 6:32206
     [Google Scholar]
131. 131. 

     Lastres-Becker I, Ulusoy A, Innamorato NG, Sahin G, Rabano A et al. 2012. α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. Hum. Mol. Genet. 21:3173–92
     [Google Scholar]
132. 132. 

     Lastres-Becker I, Garcia-Yague AJ, Scannevin RH, Casarejos MJ, Kugler S et al. 2016. Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease. Antioxid. Redox Signal. 25:61–77
     [Google Scholar]
133. 133. 

     Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA. 2010. Lysosomal degradation of α-synuclein in vivo. J. Biol. Chem. 285:13621–29
     [Google Scholar]
134. 134. 

     Pajares M, Rojo AI, Arias E, Diaz-Carretero A, Cuervo AM, Cuadrado A. 2018. Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A. Autophagy 14:1310–22
     [Google Scholar]
135. 135. 

     Hou TT, Yang HY, Wang W, Wu QQ, Tian YR, Jia JP. 2018. Sulforaphane inhibits the generation of amyloid-β oligomer and promotes spatial learning and memory in Alzheimer's disease (PS1V97L) transgenic mice. J. Alzheimer's Dis. 62:1803–13
     [Google Scholar]
136. 136. 

     Bahn G, Park JS, Yun UJ, Lee YJ, Choi Y et al. 2019. NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models. PNAS 116:12516–23
     [Google Scholar]
137. 137. 

     Uruno A, Matsumaru D, Ryoke R, Saito R, Kadoguchi S et al. 2020. Nrf2 suppresses oxidative stress and inflammation in App knock-in Alzheimer's disease model mice. Mol. Cell. Biol. 40:6e00467-19
     [Google Scholar]
138. 138. 

     Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ et al. 2019. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann. Clin. Transl. Neurol. 6:15–26
     [Google Scholar]
139. 139. 

     Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S et al. 2011. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic. Biol. Med. 51:88–96
     [Google Scholar]
140. 140. 

     Stack C, Ho D, Wille E, Calingasan NY, Williams C et al. 2010. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease. Free Radic. . Biol. Med. 49:147–58
     [Google Scholar]
141. 141. 

     Yang L, Calingasan NY, Thomas B, Chaturvedi RK, Kiaei M et al. 2009. Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLOS ONE 4:e5757
     [Google Scholar]
142. 142. 

     Ahmad R, Khan A, Lee HJ, Ur Rehman I, Khan I et al. 2020. Lupeol, a plant-derived triterpenoid, protects mice brains against Aβ-induced oxidative stress and neurodegeneration. Biomedicines 8:380
     [Google Scholar]
143. 143. 

     Yang Y, Kong F, Ding Q, Cai Y, Hao Y, Tang B. 2020. Bruceine D elevates Nrf2 activation to restrain Parkinson's disease in mice through suppressing oxidative stress and inflammatory response. Biochem. Biophys. Res. Commun. 526:1013–20
     [Google Scholar]
144. 144. 

     Liu S, Li G, Tang H, Pan R, Wang H et al. 2019. Madecassoside ameliorates lipopolysaccharide-induced neurotoxicity in rats by activating the Nrf2-HO-1 pathway. Neurosci. Lett. 709:134386
     [Google Scholar]
145. 145. 

     Tom S, Rane A, Katewa AS, Chamoli M, Matsumoto RR et al. 2019. Gedunin inhibits oligomeric Aβ_1–42-induced microglia activation via modulation of Nrf2-NF-κB signaling. Mol. Neurobiol. 56:7851–62
     [Google Scholar]
146. 146. 

     Link P, Wink M. 2019. Isoliquiritigenin exerts antioxidant activity in Caenorhabditis elegans via insulin-like signaling pathway and SKN-1. Phytomedicine 55:119–24
     [Google Scholar]
147. 147. 

     Meng X, Sun G, Ye J, Xu H, Wang H, Sun X 2014. Notoginsenoside R1-mediated neuroprotection involves estrogen receptor-dependent crosstalk between Akt and ERK1/2 pathways: a novel mechanism of Nrf2/ARE signaling activation. Free Radic. Res. 48:445–60
     [Google Scholar]
148. 148. 

     Fornes O, Castro-Mondragon JA, Khan A, van der Lee R, Zhang X et al. 2020. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res 48:D87–92
     [Google Scholar]
149. 149. 

     Hayes JD, Dinkova-Kostova AT. 2014. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39:199–218
     [Google Scholar]
150. 150. 

     Dringen R, Pfeiffer B, Hamprecht B. 1999. Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J. Neurosci. 19:562–69
     [Google Scholar]