Expression of unstable translated CAG repeats is the mutational mechanism in nine different neurodegenrative disorders. Although the products of genes harboring these repeats are widely expressed, a subset of neurons is vulnerable in each disease accounting for the different phenotypes. Somatic instability of the expanded CAG repeat has been implicated as a factor mediating the selective striatal neurodegeneration in Huntington disease. It remains unknown, however, whether such a mechanism contributes to the selective neurodegeneration in other polyglutamine diseases or not. To address this question, we investigated the pattern of CAG repeat instability in a knock-in mouse model of spinocerebellar ataxia type 1 (SCA1). Small pool PCR analysis on DNA from various neuronal and non-neuronal tissues revealed that somatic repeat instability was most remarkable in the striatum. In the two vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profiles of mosaicism. These results suggest that in SCA1, there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knock-in models of polyglutamine diseases highlights the role of trans-acting tissue- or cell-specific factors in mediating the instability.
Bibliographical noteFunding Information:
We are grateful to D. Shinde and N. Arnheim for help determining the appropriate primers for PCR reactions by performing single-sperm analysis of the Sca1154Q/2Q mice. This work is supported by grants from the National Institute of Neurological Disorders and Stroke of NIH to H.Y.Z. (NS27699) and H.T.O. (NS22920). H.Y.Z. is an Investigator and K.W. is a Postdoctoral Research Associate with the Howard Hughes Medical Institute.