From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington's disease

Huntington's disease (HD) is an inherited progressive neurodegenerative dis ease caused by the expansion of a polyglutamine repeat sequence within a no vel protein. Recent work has shown that abnormal intranuclear inclusions of aggregated mutant protein within neurons is a characteristic feature share d by HD and several other diseases involving glutamine repeat expansion. Th is suggests that in each of the these disorders the affected nerve cells de generate as a result of these abnormal inclusions. A transgenic mouse model of HD has been generated by introducing exon 1 of the HD gene containing a highly expanded CAG sequence into the mouse germline. These mice develop w idespread neuronal intranuclear inclusions and neurodegeneration specifical ly within those areas of the brain known to degenerate in HD. We have inves tigated the sequence of pathological changes that occur after the formation of nuclear inclusions and that precede neuronal cell death in these cells. Although the relation between inclusion formation and neurodegeneration ha s recently been questioned, a full characterization of the pathways linking protein aggregation and cell death will resolve some of these controversie s and will additionally provide new targets for potential therapies.