A mutation in the gene for PAK-3, a molecule that is thought to play a variety of roles in the nervous system, has been implicated in a form of X-chromosome-linked mental retardation affecting one in 100 males. People who have the mutation have a normal physical appearance, and their brains appear normal on MRI scans, yet they have profound deficits in language, cognition and social behavior. The new finding was published by Christopher Walsh and colleagues in this month's Nature Neuroscience. PAK-3 is involved in regulating neuronal shape, a process that has recently come to be recognized as one that continues in the mature, adult brain-not just during development-and probably plays an important role in learning and memory. It is not yet known how PAK-3 regulates this process, but the protein contains a kinase domain, which is altered by the mutation. The mutant PAK-3 may be unable to trigger the activity of kinases that are needed to modify the neuron's shape or activity. Fascinatingly, this is the third mutation for this form of X-linked mental retardation to be announced in the past three months. 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. Interestingly, a poster presented by Rachael Neve and colleagues at last year's Society of Neuroscience meeting reports that the 100-amino-acid C-terminus fragment (C-100) of the amyloid precursor protein binds to PAK-3 (also known as N-PAK). Neve proposes that C-100, which she thinks acts as a neurotoxin in Alzheimer's disease, causes abnormal activation of N-PAK, which is involved not only in regulating neuronal structure but may also be part of an apoptotic pathway. In either case, this new finding raises a new possibility of a common molecular factor underlying both Alzheimer disease and mental retardation. (The first such link found, of course, was between Alzheimer's disease and Down's syndrome.)-June Kinoshita.

Reference:Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA, Mulley JC, Walsh CA. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 1998 Sep;20(1): 25-30. Abstract

See also our seminar: "The role of the carboxyl-terminal fragment of APP in the neurodegeneration and cognitive loss in Alzheimer's disease," by R. Neve.