Expression of unstable translated CAG repeats is the mutational mechanism in nine different neurodegenerative 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.
The Spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative disorders characterized by a progressive and eventually fatal loss of balance and coordination. It has been identified that the mutation responsible for SCA1, the first SCA to be genetically classified. This mutational mechanism, an expansion of a CAG Trinucleotide repeat encoding glutamine in a protein (in this case, ataxin-1), turns out to cause a number of neurodegenerative diseases, among them several other SCAs and Huntington's disease. Exactly how the expanded protein causes neuronal degeneration has been the subject of intensive research for our lab and many others.
SCA1 is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a Parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. Neurologic findings tend to evolve as the disease progresses. The diagnosis of SCA1 rests upon the use of DNA-based testing to detect an abnormal CAG trinucleotide repeat expansion of the MJD gene.
