Project Summary

Marilou A. Andres, Ph.D. (Young Investigator 2004) of the University of Hawaii at Manoa, aims to assess the role in schizophrenia of the repeats of the triplet nucleotide, CAG, in the conductance calcium-activated potassium channel SK3. Some evidence points to a contribution for the repeats in the disease, while other studies do not. In the proposed project, Dr. Andres plans to determine the differences between 12 (short), 19, and 28 (long) CAG repeat lengths on the second, highly polymorphic CAG array on the N-terminus of the channel. As CAG repeats are toxic in neurodegenerative diseases, Dr. Andres hypothesizes that expanded CAG repeats in the SK3 channels may also be neurotoxic. Dr. Andres will test the "neurotoxic hypothesis" in an in vitro model by using short CAG repeat length proteins to rescue cells from possible lethal effects of long CAG repeats in the SK3 channels. Dr. Andres will construct dimers consisting of two SK3 cDNAs: one will be long (19 or 28) CAGs; the other short, (12) CAGs. Together they will create hetero-tetrameric channels. Findings should help resolve why heterozygotes who carry both short and long versions of the repeats do not have symptoms of schizophrenia; yet homozygotes who have only long version in their channels get psychotic symptoms.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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