Loss of the neuronal adhesion protein d-catenin leads to severe cognitive dysfunction

By specifically deleting the adhesion protein d-catenin, which is found exclusively in the brain, researchers at UCLA have found evidence that loss of d-catenin produces severe cognitive and synaptic dysfunction. Researchers have been particularly interested in d-catenin because clinical observations suggest it plays a critical role in brain function. Human chromosome-5 truncations that disrupt the function of the d-catenin gene correlate with the severity of mental retardation in Cri-du-Chat Syndrome; in addition, d-catenin is known to interact with Presenilin 1, the protein most often mutated in Familial Alzheimer's disease.

Despite these observations, until now there has been no evidence that specific deletions of d-catenin were sufficient to produce cognitive deficits. Also, although adhesion proteins have been shown to be critical for synaptic plasticity, a process by which brain circuits can be modified during learning, it has been unknown wether deletions of d-catenin would alter this process.

In the new work, researchers Inbal Israely and Xin Liu at UCLA show that mice with deletions of d-catenin display severe learning and memory deficits and thereby establish a causal link between deletions of d-catenin and cognitive dysfunction. This finding is particularly interesting because other adhesion proteins can be found in the brain, but only d-catenin is found specifically in neurons. The researchers also show that deletion of d-catenin produces severe deficits in short-lasting and long-lasting synaptic plasticity. In addition, they show that the synaptic composition of mutant animals is altered: the expression of several proteins involved in synaptic connectivity and plasticity is reduced in neurons from d-catenin mutant animals, possibly offering a clue to the mechanisms by which deletions of d-catenin cause synaptic and cognitive dysfunction. Ultimately, this work may facilitate the understanding of the mental retardation observed in Cri-du-Chat Syndrome and the memory deficits observed in Familial Alzheimer's disease.

Inbal Israely, Rui M. Costa, Cui Wei Xie, Alcino J. Silva, Kenneth S. Kosik, and Xin Liu: "Deletion of the Neuron-Specific Protein delta-catenin Leads to Severe Cognitive and Synaptic Dysfunction"

Publishing in Current Biology , Volume 14, Number 18, September 21, 2004, pages 1657–1663.

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