Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight into the pathogenesis of the SCA1 mutation and the intergenerational stability of trinucleotide repeats in mice, we have generated transgenic mice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmissions. While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration. These data indicate that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions.
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cated to the memory of Dr. Daniel T. Nordquist. The authors thank Dr. Dawna Armstrong for allowing us to review pathology on an 83-repeat case of SCA1 and Dr. Arthur L. Beaudet for critical reading of this manuscript and continued thoughtful discussions. This work was supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health to H. T. O and H. B. C. (NS33718), to H. Y. Z. (NS27699), and to E. N. B. (NS09724-01). A, S. was supported by an Italian Telethon Fellowship, and T. M. was supported by the Spanish Ministerio de Educacion y Ciencia (PF 94 969 798).