Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation
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 neuroinf...
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| Veröffentlicht in: | Science advances 2020-11, Vol.6 (46) |
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| creator | Nakano-Kobayashi, A Fukumoto, A Morizane, A Nguyen, D T Le, T M Hashida, K Hosoya, T Takahashi, R Takahashi, J Hori, O Hagiwara, M |
| description | 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. |
| doi_str_mv | 10.1126/sciadv.abc1428 |
| format | Article |
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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.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abc1428</identifier><identifier>PMID: 33188020</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Disease Models, Animal ; Dopaminergic Neurons - metabolism ; Mice ; Mice, Inbred C57BL ; Microglia - metabolism ; Neurodegenerative Diseases - etiology ; Neurodegenerative Diseases - metabolism ; Neurodegenerative Diseases - therapy ; Neuroinflammatory Diseases ; Neuroscience ; NF-E2-Related Factor 2 - metabolism ; SciAdv r-articles</subject><ispartof>Science advances, 2020-11, Vol.6 (46)</ispartof><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2020 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-4c176e90a9762d74f4dcf67f969facea626fa69d5edd3ea1c571e055c67014bc3</citedby><cites>FETCH-LOGICAL-c500t-4c176e90a9762d74f4dcf67f969facea626fa69d5edd3ea1c571e055c67014bc3</cites><orcidid>0000-0002-2910-0879 ; 0000-0002-7270-351X ; 0000-0002-1407-9640 ; 0000-0002-1665-3845 ; 0000-0003-1193-7571 ; 0000-0003-3642-9186 ; 0000-0003-2019-9400 ; 0000-0002-2210-0446</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673758/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673758/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33188020$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nakano-Kobayashi, A</creatorcontrib><creatorcontrib>Fukumoto, A</creatorcontrib><creatorcontrib>Morizane, A</creatorcontrib><creatorcontrib>Nguyen, D T</creatorcontrib><creatorcontrib>Le, T M</creatorcontrib><creatorcontrib>Hashida, K</creatorcontrib><creatorcontrib>Hosoya, T</creatorcontrib><creatorcontrib>Takahashi, R</creatorcontrib><creatorcontrib>Takahashi, J</creatorcontrib><creatorcontrib>Hori, O</creatorcontrib><creatorcontrib>Hagiwara, M</creatorcontrib><title>Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. 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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.</description><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microglia - metabolism</subject><subject>Neurodegenerative Diseases - etiology</subject><subject>Neurodegenerative Diseases - metabolism</subject><subject>Neurodegenerative Diseases - therapy</subject><subject>Neuroinflammatory Diseases</subject><subject>Neuroscience</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>SciAdv r-articles</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUbFO7DAQtBAIENBSopSvyWE7sZ00SE-IB0gIGqitPXt9GBIn2Al6_D2GOxBUu9LMzu7OEHLM6IIxLk-T8WBfF7A0rObNFtnnlRIlF3Wz_aPfI0cpPVFKWS2lYO0u2asq1jSU033yfP-IEUacJ29SMQ4ThsnD5MOq6L2Jw6rz0BUjZ-VtdLyA_z4VBkIRMZkZi4BzHCyuMGSVyQ8hg3NCWyzf1pgProO-_8QOyY6DLuHRph6Qh38X9-dX5c3d5fX535vSCEqnsjZMSWwptEpyq2pXW-Okcq1sHRgEyaUD2VqB1lYIzAjFkAphpMovLk11QM7WuuO87NGa_FKETo_R9xDf9ABe_0aCf9Sr4VUrqbJpTRb4sxGIw8uMadK9Twa7DgIOc9K8llRlL0WbqYs1NXuVUkT3vYZR_RGSXoekNyHlgZOfx33TvyKp3gEGpZNZ</recordid><startdate>20201113</startdate><enddate>20201113</enddate><creator>Nakano-Kobayashi, A</creator><creator>Fukumoto, A</creator><creator>Morizane, A</creator><creator>Nguyen, D T</creator><creator>Le, T M</creator><creator>Hashida, K</creator><creator>Hosoya, T</creator><creator>Takahashi, R</creator><creator>Takahashi, J</creator><creator>Hori, O</creator><creator>Hagiwara, M</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2910-0879</orcidid><orcidid>https://orcid.org/0000-0002-7270-351X</orcidid><orcidid>https://orcid.org/0000-0002-1407-9640</orcidid><orcidid>https://orcid.org/0000-0002-1665-3845</orcidid><orcidid>https://orcid.org/0000-0003-1193-7571</orcidid><orcidid>https://orcid.org/0000-0003-3642-9186</orcidid><orcidid>https://orcid.org/0000-0003-2019-9400</orcidid><orcidid>https://orcid.org/0000-0002-2210-0446</orcidid></search><sort><creationdate>20201113</creationdate><title>Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation</title><author>Nakano-Kobayashi, A ; Fukumoto, A ; Morizane, A ; Nguyen, D T ; Le, T M ; Hashida, K ; Hosoya, T ; Takahashi, R ; Takahashi, J ; Hori, O ; Hagiwara, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-4c176e90a9762d74f4dcf67f969facea626fa69d5edd3ea1c571e055c67014bc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microglia - metabolism</topic><topic>Neurodegenerative Diseases - etiology</topic><topic>Neurodegenerative Diseases - metabolism</topic><topic>Neurodegenerative Diseases - therapy</topic><topic>Neuroinflammatory Diseases</topic><topic>Neuroscience</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>SciAdv r-articles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakano-Kobayashi, A</creatorcontrib><creatorcontrib>Fukumoto, A</creatorcontrib><creatorcontrib>Morizane, A</creatorcontrib><creatorcontrib>Nguyen, D T</creatorcontrib><creatorcontrib>Le, T M</creatorcontrib><creatorcontrib>Hashida, K</creatorcontrib><creatorcontrib>Hosoya, T</creatorcontrib><creatorcontrib>Takahashi, R</creatorcontrib><creatorcontrib>Takahashi, J</creatorcontrib><creatorcontrib>Hori, O</creatorcontrib><creatorcontrib>Hagiwara, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nakano-Kobayashi, A</au><au>Fukumoto, A</au><au>Morizane, A</au><au>Nguyen, D T</au><au>Le, T M</au><au>Hashida, K</au><au>Hosoya, T</au><au>Takahashi, R</au><au>Takahashi, J</au><au>Hori, O</au><au>Hagiwara, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2020-11-13</date><risdate>2020</risdate><volume>6</volume><issue>46</issue><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. 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| subjects | Animals Disease Models, Animal Dopaminergic Neurons - metabolism Mice Mice, Inbred C57BL Microglia - metabolism Neurodegenerative Diseases - etiology Neurodegenerative Diseases - metabolism Neurodegenerative Diseases - therapy Neuroinflammatory Diseases Neuroscience NF-E2-Related Factor 2 - metabolism SciAdv r-articles |
| title | Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation |
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