UCSD researchers describe cell activity leading to disruption of neuron...( An interaction between two brain protei...),Health

The studies in mice, conducted in the lab of Joseph G. Gleeson, M.D., UCSD assistant professor of neurosciences, combines work in both humans and mice to identify a protein kinase called Cdk5 as the "off" switch for a crucial neuronal migration protein called doublecortin. When Cdk5 adds a phosphate molecule to doublecortin, the doublecortin is inactivated and neuronal migration is arrested.

In the normal brain, neurons are born deep within fluid filled cavities of the brain during the third and fourth month of gestation. Then, they must migrate hundreds of cell-body distances to reach their proper position within the six-layered cortex. When this migration is defective and neurons are stopped short of their destination, there is an absence of the normal grooves and ridges that characterize the brain in higher mammals.

A severe brain disorder in newborns, called lissencephaly, or "smooth brain," is a result of abnormal neuronal migration where only four, instead of six layers of cortex are formed. Those children who survive the mutation suffer from profound mental retardation, epilepsy and cerebral palsy. Gleeson and colleagues previously showed that mutations in the doublecortin gene account for approximately 20 percent of the cases of lissencephaly in humans.

The study concluded that Cdk5 phosphorylation and inactivation of doublecortin takes place normally in the developing brain, but that it is balanced by reactivation of doublecortin by an as-yet-unidentified "on" switch. It appears that the regulation of this phosphorylation is critical for migration, and that both inactivation and reactivation are required for the normal functioning of the protein. Gleeson'
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Contact: Sue Pondrom
spondrom@ucsd.edu
619-543-6163
University of California - San Diego
21-Jan-2004