Abnormal Alternative Splicing and Schizophrenia

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

DESCRIPTION (provided by applicant): Hakak et al. 2001 conducted a microarray experiment to measure changes in gene expression between postmortem samples of dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia (SCZ) and matched controls. Their most striking finding was that a group of myelin-related genes were down-regulated, as well as genes involved in RNA splicing/processing (RSPs) and neuronal signaling. Dysregulation of genes in these categories have been roughly reproducible in independent SCZ/DLPFC arrays although fold changes are generally small. Subsequently numerous investigators have documented abnormally distributed and decreased numbers of oligodendrocytes in the SCZ/DLPFC region yet it seems that cell loss alone cannot account for decreased expression of Dr. Hakak's myelin genes because expression of other oligodendroctye genes are not reduced. In order to translate this array data into pathophysiology we need to understand how such small changes in mRNA expression might cause damage at the protein level and how these changes could occur with regional and cellular specificity. We also need to look for novel regulatory networks that could be coordinating changes in gene expression between and within gene families. In this proposal we suggest that abnormal alternative splicing of pre-mRNA (AS) could at least partially account for cell specific damage despite small changes in total RNA. Moreover, RSPs govern AS and form regulatory networks that could easily link the changes in myelin and neuronal signaling genes. To test our hypothesis we will extract RNA from the same case and control DLPFC tissue used in the original Hakak et al. experiment and hybridize it to a custom microarray designed specifically for detecting alternative mammalian splice forms in a high-throughput fashion.