BEHAVIORAL ABNORMALITIES AND SELECTIVE NEURONAL LOSS IN HD TRANSGENICMICE EXPRESSING MUTATED FULL-LENGTH HD CDNA

Huntington disease (HD) is an adult-onset, autosomal dominant inherite d human neurodegenerative disorder characterized by hyperkinetic invol untary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuro n loss and gliosis in striatum. cerebral cortex, thalamus, subthalamus and hippocampus(1-4) are well recognized as neuropathological correla tes for the clinical manifestations of HD. The underlying genetic muta tion is the expansion of CAG trinucleotide repeats (coding for polyglu tamines) to 36-121 copies in exon 1 of the HD gene(5-8). The HD mRNA a nd protein product (huntingtin) show widespread distribution(9-11), an d thus much remains to be understood about the selective and progressi ve neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of f ull-length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mi ce with 48 or 89 CAG repeats manifested progressive behavioural and mo tor dysfunction with neuron loss and gliosis in striatum, cerebral cor tex, thalamus and hippocampus. These animals represent clinically rele vant models for HD pathogenesis, and may provide insights into the und erlying pathophysiological mechanisms of other triplet repeat disorder s.