Transgenic models of Huntington's disease

1Huntington's disease (HD) is an inherited neurodegenerative disorder cause d by a CAG-polyglutamine repeat expansion. A mouse model of this disease ha s been generated by the introduction of exon 1 of the human HD gene carryin g highly expanded CAG repeats into the mouse germ line (R6 lines). Transgen ic mice develop a progressive neurological phenotype with a movement disord er and weight loss similar to that in HD. We have previously identified neu ronal inclusions in the brains of these mice that have subsequently been es tablished as the pathological hallmark of polyglutamine disease. Inclusions are present before symptoms, which in turn occur long before any selective neuronal cell death can be identified. We have extended the search for inc lusions to skeletal muscle, which, like brain, contains terminally differen tiated cells. We have conducted an investigation into the skeletal muscle a trophy that occurs in the R6 lines, (i) to provide possible insights into t he muscle bulk loss observed in HD patients, and (ii) to conduct a parallel analysis into the consequence of inclusion formation to that being perform ed in brain. The identification of inclusions in skeletal muscle might be a dditionally useful in monitoring the ability of drugs to prevent inclusion formation in vivo.