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Christopher A. Walsh Laboratory 

Focus - September 4th, 1998

Finding Mental Retardation Gene Supports New View of Learning and Memory

By Misia Landau

A gene mutation responsible for a form of inherited mental retardation in males has been located on the X chromosome, report researchers from Harvard Medical School and other institutions in the September Nature Genetics. The discovery offers a new perspective on how neurons interact in learning and memory because the defect, which causes severe cognitive problems, was found on a gene that normally regulates neuron shape.

Traditionally, mature neurons were thought to convey messages by changing their chemical and electrical properties without any change of shape. "Previously, people had only static pictures--electron micrographs and the like--and it appeared that the neuron gets set up during development and that's it," says Christopher Walsh, associate professor of neurology at HMS and Beth Israel Deaconess.

Using more advanced techniques, researchers have begun to see that electrical transmission is accompanied by movement at the tiny spines located along the neuron's receiving arms, or dendrites. The spines, which accept input from the axons of other nerve cells, appear to contract and expand--increasing or decreasing electrical resistance and, in turn, the ease with which the dendrites conduct electrical impulses.

"So a neuron can sort of tune in one synapse and tune out another by changing the shape of the spine," says Walsh who, with HMS colleagues Kristina Allen and Joseph Gleeson, instructors in neurology at BID and Children's Hospital, respectively, discovered the new X-linked mental retardation mutant. As it turns out, the defect, which occurs in the PAK3 gene, is the third mutation for this particular form of X-linked mental retardation, called nonsyndromic mental retardation (MRX), to be announced in the past three months. Intriguingly, two of the three mutations occur in genes that control cell shape and that may be part of the same signaling pathway in the neuron.

Walsh and his colleagues do not yet know if the newly discovered PAK3 mutation impairs a neuron's ability to change shape--or if it causes physical defects of any kind. The magnetic resonance image of the brain of one person carrying the mutant PAK3 appears normal. Yet such gross images would not reveal defects in cell shape, Walsh says.

In general, the appearance of MRX males is misleading. Despite their profound behavioral disabilities--delayed and primitive speech as well as severe learning and social impairments--most of the one in 600 males affected look remarkably normal. Unlike other forms of retardation, which entail problems in several organs, MRX appears to affect only the brain--which is why MRX genes have been so prized by neurobiologists.

Chasing a Different Quarry

Walsh and his colleagues initially thought mutations in PAK3 might be responsible for a different disorder, called doublecortex. Though their research ruled that out, they still believed that a PAK3 mutant might cause some other inherited neurological disease. Allen, who is a Goldenson-Berenberg postdoctoral fellow at HMS, consulted an international genetic database and found that four MRX families had mutations mapping to the region of the X chromosome where PAK3 lies. She found one of the families carried a PAK3 mutant. The mutation was small--a single base change. But it turned a normal coding amino acid into a stop codon, the equivalent of a genetic red light.

Normally, the PAK3 protein consists of two domains--a binding and an activating domain. In its healthy state, the PAK3 protein acts as a kind of middleman, shuttling between small G proteins, which it binds, and cytoskeletal proteins (such as myosin, actin, and microtubulin), which it activates (see illustration). The stop codon occurred in the middle of the second, or kinase, domain. When Allen and her colleagues put the defective PAK3 gene into cultured cells, only the first half of the protein was functional. The protein showed no kinase activity.

It is not clear exactly how the defective PAK3 protein interferes with the normal functioning of the nerve cell to cause MRX. One possibility is that it binds small G proteins but, lacking its kinase domain, is unable to activate cytoskeletal proteins. "So it hooks up to the G protein but has nowhere to go because its kinase activity is dead," Walsh says. If so, it could prevent the small G proteins from doing other things--and small G proteins typically act as launching sites for a whole series of signal cascades. "So it could gum up the works," he says.

This scenario suggests one approach to treating people with MRX would be to target kinases. "If the kinase is dead or partially functional, we might try to boost the activity," says Walsh. Yet he cautions they will need to know much more about how PAK3 works before they tinker with kinases or anything else.

This research was funded in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and the Human Frontier Science Program.


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