FORMATION OF NEURONAL INTRANUCLEAR INCLUSIONS UNDERLIES THE NEUROLOGICAL DYSFUNCTION IN MICE TRANSGENIC FOR THE HD MUTATION

Huntington's disease (HD) is one of an increasing number of human neur odegenerative disorders caused by a CAG/polyglutamine-repeat expansion . The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for th e delayed onset, selective pattern of neuropathology, and cell death o bserved in HD has not been described. We have observed that mice trans genic for exon 1 of the human Ho gene carrying (GAG)(115) to (CAG)(156 ) repeat expansions develop pronounced neuronal intranuclear inclusion s, containing the proteins huntingtin and ubiquitin, prior to developi ng a neurological phenotype. The appearance in transgenic mice of thes e inclusions, followed by characteristic morphological change within n euronal nuclei, is strikingly similar to nuclear abnormalities observe d in biopsy material from HD patients.