DISCOVERY OF CRUCIAL PROTEIN INTERACTION SHEDS LIGHT ON MENTAL RETARDATION
Failure of PAK1 to interact with zebrafish protein FXR1 suggests a likely cause of fragile X syndrome
1. A team of scientists from the Agency for Science, Technology and Research (A*STAR) is the first to discover a crucial interaction between the protein kinase PAK1, which plays a key role in the formation of synapses in the brain, and the fragile-X-related, or FXR1, protein. This breakthrough, published in the leading journal Molecular Cell, sheds light on the molecular mechanisms underlying fragile X syndrome , the most common cause of inherited male mental retardation and a leading genetic determinant of autism, and may lead to a better understanding of the complex causes of this disease.
2. The scientists, led by Prof Edward Manser from A*STAR’S Institute of Medical Biology (IMB) and the A*STAR-Duke-NUS Graduate Medical School Neuroscience Research Partnership (A*STAR-Duke-NUS GMS NRP) discovered that PAK1 plays a direct role in activating FXR1. By studying the interaction between these two proteins, the scientists were better able to understand the interactions between PAK1 and another protein FMR1. FMR1, or fragile-X mental retardation protein, is a protein that is structurally similar to FXR1 and is critical for proper neural development.
3. “The chance discovery that PAK1 also interacted with FXR1 provided us with an excellent opportunity to study the FMR1 protein: directly studying the FMR1 protein is problematic because its effects on brain function are difficult to measure. The well-known FXR1 provides a much easier way to understand the workings of FMR1 because its effects are more visible,” explained Prof Manser.
4. Using zebrafish, the scientists showed that if PAK1 is unable to interact with FXR1, muscular development in the fish goes awry. As FXR1 and FMR1 are highly similar, this result suggests that the inability of PAK1 to connect to mutant FMR1 is a key facet of the fragile X syndrome.
5. Prof Manser and his team plan to build upon their discovery by further investigating the interplay between PAK1 and associated proteins in synapses so as to shed more light on fragile X syndrome.
6. Said Prof Dale Purves, Director of the Neurosciences and Behavioral Disorders Program at Duke-NUS Graduate Medical School and Executive Director of A*STAR-Duke-NUS GMS NRP, “This study by Ed Manser and his group is a fine example of how basic research contributes to understanding processes that lead to devastating neurological disorders. The causes of mental retardation remain obscure at the cellular and molecular level, and this sort of painstaking research is really the only way forward.”
7. Prof Birgit Lane, Executive Director of IMB, added, “This paper by Ed Manser and colleagues is a great example of the kind of work we aspire to do in IMB - to understand the mechanisms underlying human disease so that we can come up with new approaches to combating illness. We are very proud of Ed and the team.”
8. Prof Manser isolated the kinase PAK1 in 1994 while working at the Institute of Molecular and Cell Biology (IMCB), under the GSK-IMCB research fund. This ground-breaking work published in Nature is one of the most highly cited papers in basic biology from Singapore. The GSK-IMCB group has built an International reputation in cell signaling. In April 2009 they joined the A*STAR-NRP as part of a core effort in developing basic neuroscience at Biopolis.
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Notes to the Editor:
The research findings described in the press release can be found in the following article, "A functional requirement for PAK1 binding to the KH(2) domain of the fragile X protein-related FXR1", published in the 23 Apr 2010 print issue of Molecular Cell.
Authors: Evonne SAY1,5, Hwee-Goon TAY2,5, Zhuo-shen ZHAO1, Yohendran BASKARAN1, Li RONG4, Louis LIM3 and Ed MANSER1,2,#
1 Neuroscience Research Partnership, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673
2 Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore
3 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 1PJ,
United Kingdom
4 Experimental Therapeutics Centre (ETC), Agency for Science, Technology and Research (A*STAR), Singapore.
5 These authors contributed equally to the work.
# Corresponding author:
Prof Ed Manser, ed.manser@imb.a-star.edu.sg
About the Institute of Medical Biology (IMB)
The Institute of Medical Biology is a member of the Agency for Science, Technology and Research (A*STAR). It was formed in 2007, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life. Its research focus areas are in stem cells, genetic diseases, epithelial and neurobiology, cancer, and control of differentiation. IMB is developing internationally excellent research programmes working closely with clinical collaborators, targeting the challenging interface between basic science and clinical medicine, and aiming to promote increased and effective throughput of research from bench to bedside. Its growing portfolio of strategic research topics aims to promote translational research on the mechanisms of human diseases with a cell to tissue emphasis that can help identify new therapeutic strategies for disease amelioration, cure and eradication.
For more information about IMB, please visit www.imb.a-star.edu.sg.
About the Institute of Molecular and Cell Biology (IMCB)
The Institute of Molecular and Cell Biology (IMCB) is a member of Singapore’s Agency for Science, Technology and Research (A*STAR) and is funded through A*STAR’s Biomedical Research Council (BMRC). It is a world-class research institute that focuses its activities on six major fields: Cell Biology, Developmental Biology, Genomics, Structural Biology, Infectious Diseases, Cancer Biology and Translational Research, with core strengths in cell cycling, cell signalling, cell death, cell motility and protein trafficking. Its achievements include leading an international consortium that successfully sequenced the entire pufferfish (fugu) genome. The IMCB was awarded the Nikkei Prize 2000 for Technological Innovation in recognition of its growth into a leading international research centre and its collaboration with industry and research institutes worldwide. Established in 1987, the Institute currently has 35 independent research groups with more than 400 staff members.
For more information about IMCB, please visit www.imcb.a-star.edu.sg
About the Agency for Science, Technology and Research (A*STAR)
A*STAR is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and nine consortia & centres, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.
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