Scientific Report 2005

Molecular Biology

Molecular Neurobiology of CNS Disorders

E.A. Thomas, J.G. Sutcliffe, P.A. Desplats, S. Narayan, K.E. Kass, W. Huang

Gene Expression in Striatal Disorders

We have identified and cataloged approximately 50 genes that are predominantly expressed in the striatum in the brain. Our long-standing hypothesis is that such genes most likely encode proteins that are preferentially associated with particular physiologic processes in the striatum and therefore may be relevant to striatal disorders. Using oligonucleotide microarrays, we measured expression of these genes simultaneously in the striatum of R6/1 mice, a transgenic model of Huntington’s disease.

A total of 81% of striatal genes had increased expression in mice in presymptomatic and/or symptomatic stages of illness. Changes in expression of genes associated with G protein signaling and calcium homeostasis are of particular interest for future studies. The most striking decrease occurred in β4, a newly identified subunit of the sodium channel. Changes in expression began when the mice were 8 weeks old, and expression had progressively decreased almost 10-fold by the time the mice were 8 months old. Two novel sequences with highly specific striatal expression also had differences in expression throughout the life span of the mutant mice, as determined by in situ hybridization analysis.

Expression differences of 15 of the striatum-enriched genes were tested in rats treated with 6-hydroxydopamine, a rodent model of Parkinson’s disease. No changes in expression were detected in any of the genes tested.

These findings indicate that mutant huntingtin protein causes selective deficits in the expression of mRNAs responsible for striatum-specific physiologic changes. Furthermore, the results suggest that although both Huntington’s disease and Parkinson’s disease involve striatal dysfunction, the differences in the molecular pathologic changes associated with the 2 diseases are distinct.

Molecular Markers of Schizophrenia

Schizophrenia is a life-long mental illness with variable expression and unknown etiology. The major clinical manifestations of schizophrenia at the time of onset of the illness are psychotic symptoms; however, as the illness progresses, the negative symptoms become more predominant. In addition, many other neurologic aspects change during the course of the illness. We are interested in the molecular factors that influence manifestation of the symptoms and the course of schizophrenia after its onset and how treatment modifies the effects of illness.

Using oligonucleotide microarrays, we generated gene expression profiles from tissue samples obtained at autopsy from the prefrontal cortex of patients with schizophrenia of short and long duration. Because correct treatment early in the illness is thought to have a beneficial effect on the outcome of schizophrenia, the identification of genes involved in the early and late stages of disease will be important for understanding the progression of the illness.

Publications

Dean, B., Keriakous, D., Thomas, E.A., Scarr, E. Understanding the pathology of schizophrenia: the impact of high-throughput screening of the genome and proteome in postmortem CNS. Curr. Psychiatry Rev. 1:1, 2005.

Digney, A., Keriakous, D., Scarr, E., Thomas, E.A., Dean, B. Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. Biol. Psychiatry 57:711, 2005.

Yao, J.K., Thomas, E.A., Reddy, R.D., Keshavan, M.S. Association of plasma apolipoproteins D with RBC membrane arachidonic acid levels in schizophrenia. Schizophr. Res. 72:259, 2005.

Ziolkowska, B., Gieryk, A., Bilecki, W., Wawrzczak-Bargiela, A., Wedzony, K., Chocyk, A., Danielson, P.E., Thomas, E.A., Hilbush, B.S., Sutcliffe, J.G., Przewlocki, R. Regulation of α-synuclein expression in limbic and motor brain regions of morphine-treated mice. J. Neurosci. 25:4996, 2005.