Failure of PAK1 to interact with zebrafish protein FXR1 suggests a likely cause of fragile X syndrome.

A team of scientists1 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 synapses2 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 syndrome3, 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.

The scientists, led by Prof Edward Manser4 from A*STAR’S Institute of Medical Biology (IMB) and the A*STAR-Duke-NUS Graduate Medical School Neuroscience Research Partnership5 (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

“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.

Using zebrafish, the scientists showed that if PAK1 is unable to interact with FXR1, muscular development in the fish goes awry. As FXR1 and FMR16 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. 

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.

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.”

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.”

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 Nature7 is one of the most highly cited papers8 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.

 

1 The team is made up of scientists from the Institute of Molecular and Cell Biology (IMCB), the Institute of Medical Biology (IMB), and the Experimental Therapeutics Centre (ETC) under the Agency for Science, Technology and Research (A*STAR), and the University College London (UCL) Institute of Neurology.

2 Synapses are the junctions where two neurons, or nerve cells, meet.

3 Fragile X syndrome is responsible for disabilities ranging from learning difficulties to more severe mental impairment.

4 Prof Manser currently holds appointments at two A*STAR institutes: the Institute of Molecular and Cell Biology and the Institute of Medical Biology.

5 The partnership was initiated in October 2007 and aims to establish an integrated, multidisciplinary programme in neuroscience with a strong focus on translational research.

6 The scientists determined that a region, known as the KH(2) domain, is shared by both FXR1 and FMR1 and is key to their interaction with PAK1.

7 E. Manser, T. Leung, H. Salihuddin, Z. S. Zhao and L. Lim. (1994) A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367 : 40-46.

8 According to ScienceWeb, the paper has been cited 958 times to date.

Publication:
"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.
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.

Contact: Joshua Tan, Corporate Communications, A*STAR, Tel: (65) 6826 6353, Email: joshua_tan@a-star. edu. sg

Source: Agency for Science, Technology and Research (A*STAR)

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