Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD patients

Huntington's disease (HD) is a progressive neurological disorder caused by a CAG/polyglutamine repeat expansion. We have previously generated the R6/2 mouse model that expresses exon 1 of the human HD gene containing CAG repe ats in excess of 150. These mice develop a progressive neurological phenoty pe with a rapid onset and progression. We show here that it is impossible t o establish fibroblast lines from these mice at 12 weeks of age, whilst thi s can be achieved without difficulty at 6 and 9 weeks. Cultures derived fro m mice at 12 weeks contained a high frequency of dysmorphic cells, includin g cells with an aberrant nuclear morphology and a high frequency of micronu clei and large vacuoles. All of these features were also present in a line derived from a juvenile HD patient. Fibroblast lines derived from R6/2 mice and from HD patients were found to have a high frequency of multiple centr osomes which could account for all of the observed phenotypes including a r educed mitotic index, high frequency of aneuploidy and persistence of the m idbody. We were unable to detect large insoluble polyglutamine aggregates i n either the mouse or human lines. We have identified a novel progressive H D pathology that occurs in cells of non-central nervous system origin. An i nvestigation of the pathological consequences of the HD mutation in these c ells will provide insight into cellular basis of the disease.