Research delves into role of key proteins in fragile X syndrome: study explores relationship between enzymes, FXS symptoms; identifies candidate drug for targeted treatment.

Abstract

American Journal of Medical Genetics Part AVolume 167, Issue 3 p. ix-ix the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah LevensonFree Access Research delves into role of key proteins in fragile X syndrome Study explores relationship between enzymes, FXS symptoms; identifies candidate drug for targeted treatment First published: 18 February 2015 https://doi.org/10.1002/ajmg.a.37020AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat A recent paper adds to a growing body of scientific evidence that suggests eliminating a specific enzyme can improve symptoms of fragile X syndrome (FXS) and proposes an experimental medication to do the job. FXS, which results from mutations in the FMR1 gene, is the most common genetic culprit in autism and intellectual disability and also causes anxiety and seizures. Psychiatric drugs and other medications can manage some symptoms, but treatments that target the genetic and protein abnormalities underlying FXS are lacking. In a study published in Cell Reports, investigators from McGill University in Montreal and University of Edinburgh in Scotland support research based on animal studies that show the interaction between particular proteins plays a significant role in the development of autistic behaviors and irregular synapses, which connect the brain's nerve cells (Gkogkas et al., 2014). Co–first author Christos G. Gkogkas, PhD, and colleagues focus on two proteins: matrix metallopeptidase 9 (MMP-9), which breaks down and reorders synapses, and eukaryotic translation initiation factor 4E (eIF4E), which regulates MMP-9. Dr. Gkogkas is Chancellor's Fellow at the Centre for Integrative Physiology and The Patrick Wild Centre at University of Edinburgh in Scotland. In normal mice, MMP-9 secreted into synapses remains largely inactive,whereas mice genetically engineered to have FXS symptoms have higher levels of active MMP-9. The researchers found that mice genetically engineered to lack FMR1 and produce less of the protein eIF4E had lower levels of active MMP-9. When eIF4E levels decrease, so do levels of MMP-9. Link with Protein Synthesis Gkogkas et al. write that MMP-9 may be connected to synthesis of other proteins important to the maturation and function of synapses, and they suggest restoring normal MMP-9 activity may impact production of these other proteins and possibly improve symptoms of FXS. The interaction between particular proteins in brain synapses (depicted above) may contribute to the development of autistic behaviors and irregular brain-cell function. While other studies have shown a relationship between eIF4E and MMP-9, the research by Gkogkas et al. demonstrates, for the first time, that brain samples from deceased FXS patients and brain regions from FXS model mice each have increased levels of MMP-9. The paper also provides the first evidence that the experimental antifungal drug cercosporamide, which has been used in cancer research, is worth exploring as a targeted treatment for FXS. The team found that cercosporamide blocks eIF4E phosphorylation, which reduced levels of MMP-9 and behavioral symptoms in FXS mice. However, the researchers caution that it remains to be seen whether cercosporamide could be a viable candidate drug for people because of potential toxicity concerns. “Ours is a proof-of-principle paper for cercosporamide,” says the study's co–first author Nahum Sonenberg, PhD, a James McGill Professor in the Department of Biochemistry and the Rosaline and Morris Goodman Cancer Centre at McGill University. “We show that FXS mice can benefit from anticancer drugs,” he says, adding that he isn't yet sure if cercosporamide is worthy of more study or if a similar forthcoming drug may be better. The paper adds to prior evidence that MMP-9 is a worthy target for FXS drug research and plays a critical role in the development of autistic behaviors and synapse irregularities (Sidhu et al., 2014). Randi Hagerman, MD, Medical Director of the MIND Institute (Medical Investigation of Neurodevelopmental Disorders) at the University of California at Davis agrees, saying, “The real point of this paper is that lowering MMP is quite helpful in FXS.” References Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille JC, Sonenberg N. 2014. Pharmacogenetic inhibition of eIF4Edependent mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep 11; 9(5): 1742– 1755. Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. 2014. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model. J Neurosci 34(30): 9867– 9879. Volume167, Issue3March 2015Pages ix-ix ReferencesRelatedInformation