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Author |
Deacon, R.M.J.; Hurley, M.J.; Rebolledo, C.M.; Snape, M.; Altimiras, F.J.; Farias, L.; Pino, M.; Biekofsky, R.; Glass, L.; Cogram, P. |
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Title |
Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566 |
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Year |
2017 |
Publication |
Genes Brain And Behavior |
Abbreviated Journal |
Genes Brain Behav. |
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Volume |
16 |
Issue |
7 |
Pages |
1-10 |
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Keywords |
Autism spectrum disorder; behavior; E-cadherin; Fmr1 knockout mouse; fragile X syndrome; GST-alpha 1; NNZ2566; NQO1; Nrf2/ARE pathway; oxidative stress |
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Abstract |
Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders, fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism. Progress in basic neuroscience has led to identification of molecular targets for treatment in FXS; however, there is a gap in translation to targeted therapies in humans. This study introduces a novel therapeutic target for FXS, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor known to induce expression of over 100 cytoprotective genes. We also show that NNZ2566, a drug that has successfully completed a phase 2 clinical trial in FXS, is effective in modulating this target in FXS, partially reversing the FXS phenotype; NNZ2566 has a therapeutic role as Nrf2 activator. Effectively, treatment with NNZ2566 normalizes the translocation of Nrf2 to the nucleus, inducing expression of numerous oxidative stress-related genes including NQO1 (NAD(P) H dehydrogenase quinone 1), GST-alpha 1 (glutathione S-transferase alpha-1) and EH (epoxide hydrolase) and has a knockdown effect on E-cadherin. In summary, the Nrf2/ARE (antioxidant response element) pathway appears to be a novel promising therapeutic target for FXS and NNZ2566 appears to be acting as an activator of the Nrf2/ARE pathway and suggests a potential benefit across multiple symptoms that could be associated with the pathobiological processes underlying FXS. |
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Address |
[Deacon, R. M. J.; Altimiras, F. J.; Farias, L.; Pino, M.; Cogram, P.] Fraunhofer Res Fdn, Biomed Div, Ctr Syst Biotechnol, Santiago, Chile, Email: robertmj.deacon@gmail.com; |
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Publisher |
Wiley |
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Language |
English |
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ISSN |
1601-1848 |
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Notes |
WOS:000410314200008 |
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Call Number |
UAI @ eduardo.moreno @ |
Serial |
861 |
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