Therapeutics Potentiating Microglial P21-Nrf2 Axis Can Rescue Neurodegeneration Caused by Neuroinflammation

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Nov 14

PMID 33188020

Citations 17

Authors

A Nakano-Kobayashi

A Fukumoto

A Morizane

D T Nguyen

T M Le

K Hashida

T Hosoya

R Takahashi

J Takahashi

O Hori

M Hagiwara

Affiliations

Soon will be listed here.

Abstract

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell-derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

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References

Thimmulappa R, Lee H, Rangasamy T, Reddy S, Yamamoto M, Kensler T . Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006; 116(4):984-95. PMC: 1421348. DOI: 10.1172/JCI25790. View

Cuadrado A, Rojo A, Wells G, Hayes J, Cousin S, Rumsey W . Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019; 18(4):295-317. DOI: 10.1038/s41573-018-0008-x. View

Staurengo-Ferrari L, Badaro-Garcia S, Hohmann M, Manchope M, Zaninelli T, Casagrande R . Contribution of Nrf2 Modulation to the Mechanism of Action of Analgesic and Anti-inflammatory Drugs in Pre-clinical and Clinical Stages. Front Pharmacol. 2019; 9:1536. PMC: 6337248. DOI: 10.3389/fphar.2018.01536. View

Jazwa A, Rojo A, Innamorato N, Hesse M, Fernandez-Ruiz J, Cuadrado A . Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal. 2011; 14(12):2347-60. DOI: 10.1089/ars.2010.3731. View

Hickman S, Izzy S, Sen P, Morsett L, El Khoury J . Microglia in neurodegeneration. Nat Neurosci. 2018; 21(10):1359-1369. PMC: 6817969. DOI: 10.1038/s41593-018-0242-x. View

Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y . Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Reports. 2014; 2(3):337-50. PMC: 3964289. DOI: 10.1016/j.stemcr.2014.01.013. View

Heneka M, Kummer M, Latz E . Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014; 14(7):463-77. DOI: 10.1038/nri3705. View

Rada P, Rojo A, Chowdhry S, McMahon M, Hayes J, Cuadrado A . SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol. 2011; 31(6):1121-33. PMC: 3067901. DOI: 10.1128/MCB.01204-10. View

Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel J . Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999; 13(1):76-86. PMC: 316370. DOI: 10.1101/gad.13.1.76. View

10.

Gilhus N, Deuschl G . Neuroinflammation - a common thread in neurological disorders. Nat Rev Neurol. 2019; 15(8):429-430. DOI: 10.1038/s41582-019-0227-8. View

11.

Li S, Wang Y, Qi S, Zhang Y, Deng G, Ding W . Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice. Front Pharmacol. 2018; 9:346. PMC: 5932362. DOI: 10.3389/fphar.2018.00346. View

12.

Bodea L, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R . Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci. 2014; 34(25):8546-56. PMC: 6608212. DOI: 10.1523/JNEUROSCI.5002-13.2014. View

13.

Niu X, Yao Q, Li W, Zang L, Li W, Zhao J . Harmine mitigates LPS-induced acute kidney injury through inhibition of the TLR4-NF-κB/NLRP3 inflammasome signalling pathway in mice. Eur J Pharmacol. 2019; 849:160-169. DOI: 10.1016/j.ejphar.2019.01.062. View

14.

Satoh T, Lipton S . Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. F1000Res. 2017; 6:2138. PMC: 5730864. DOI: 10.12688/f1000research.12111.1. View

15.

Haugwitz M, Nourzaie O, Gandlur S, Sagawa H . ProteoTuner: a novel system with rapid kinetics enables reversible control of protein levels in cells and organisms. Biotechniques. 2008; 44(3):432-3. DOI: 10.2144/000112825. View

16.

Rojo de la Vega M, Chapman E, Zhang D . NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018; 34(1):21-43. PMC: 6039250. DOI: 10.1016/j.ccell.2018.03.022. View

17.

Liu F, Liang Z, Wegiel J, Hwang Y, Iqbal K, Grundke-Iqbal I . Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 2008; 22(9):3224-33. PMC: 2518253. DOI: 10.1096/fj.07-104539. View

18.

Nakagawa M, Taniguchi Y, Senda S, Takizawa N, Ichisaka T, Asano K . A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. Sci Rep. 2014; 4:3594. PMC: 3884228. DOI: 10.1038/srep03594. View

19.

Cloer E, Goldfarb D, Schrank T, Weissman B, Major M . NRF2 Activation in Cancer: From DNA to Protein. Cancer Res. 2019; 79(5):889-898. PMC: 6397706. DOI: 10.1158/0008-5472.CAN-18-2723. View

20.

Canela A, Maman Y, Huang S, Wutz G, Tang W, Zagnoli-Vieira G . Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity. Mol Cell. 2019; 75(2):252-266.e8. PMC: 8170508. DOI: 10.1016/j.molcel.2019.04.030. View