MURINE MODEL OF HEREDITARY ATAXIA SCA1

Recently, in collaboration with Dr. Huda Zohgbi (Baylor) we showed that spinocerebellar ataxia type 1 (SCA1) is due to an expansion of an unstable CAG repeat within the ataxin-1 gene on human chromosome 6p. The goal of the work proposed in this project is to study the biology of the ataxin-1 gene in the mouse. This will be achieved by: 1) Examining the tissue and developmental pattern of ataxin-1 expression in the mouse using in situ hybridization, and 2) The development and characterization of a mouse model of SCA1. Our laboratory has considerable expertise in the use of transgenic mice to study cerebellar Purkinje cells (a major site of cellular degeneration in individuals affected with SCA1). Thus, we are positioned to determine if transgenic mice expressing an expanded allele of the SCA1 gene are a suitable model of, 1) the human disease, and 2) a genetically unstable CAG repeat. A mouse model of SCA1 will provide valuable information concerning the function of ataxin-1 gene in normal cerebellar physiology, the pathologenesis of SCA1. Transgenic mice, carrying human ataxin-1 genes with various CAG repeat configurations, will also be examined as possible models for unstable (intergenerational) trinucleotide repeats.