Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA.

Huntington disease (HD) is an adult-onset, autosomal dominant inherited human neurodegenerative disorder characterized by hyperkinetic involuntary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus and hippocampus are well recognized as neuropathological correlates for the clinical manifestations of HD. The underlying genetic mutation is the expansion of CAG trinucleotide repeats (coding for polyglutamines) to 36-121 copies in exon 1 of the HD gene. The HD mRNA and protein product (huntingtin) show widespread distribution, and thus much remains to be understood about the selective and progressive neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of full-length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus and hippocampus. These animals represent clinically relevant models for HD pathogenesis, and may provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.