|   | 
Author (up) 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.
Title Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566 Type
Year 2017 Publication Genes Brain And Behavior Abbreviated Journal Genes Brain Behav.
Volume 16 Issue 7 Pages 1-10
Keywords Autism spectrum disorder; behavior; E-cadherin; Fmr1 knockout mouse; fragile X syndrome; GST-alpha 1; NNZ2566; NQO1; Nrf2/ARE pathway; oxidative stress
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.
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;
Corporate Author Thesis
Publisher Wiley Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1601-1848 ISBN Medium
Area Expedition Conference
Notes WOS:000410314200008 Approved
Call Number UAI @ eduardo.moreno @ Serial 861
Permanent link to this record