Characterisation of the anatomy and neurochemistry of the basal ganglia in a transgenic sheep model of Huntington's disease

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a single gene mutation; an expanded polyglutamine repeat on the IT15 gene. The key neuropathological features of HD are cell loss and tissue atrophy, as well as intranuclear inclusions, primarily in the basal ganglia and cortex. HD is characterised by motor dysfunction, cognitive decline, and emotional and psychiatric disorder. Currently there is no effective treatment or cure for this devastating disease. In order to enable study of the earliest disease processes and assess safety and efficacy of potential therapies of HD, our group developed an ovine model of HD. The sheep model of HD is the only large animal model to express the full-length human HD gene containing 73 polyglutamine-encoding repeats. These HD sheep display early neuropathological and behavioural features of HD. The results of the studies presented in this thesis reveal that the normal sheep substantia nigra, a key component of the basal ganglia circuit, reflects the fundamental anatomical features of the human substantia nigra. In the normal sheep striatum, the striosome and matrix compartments reflect certain neurochemical features of the human brain, but also display some unique neurochemical expression patterns. In addition, this thesis investigates neuropathology in the substantia nigra, and the striosome and matrix compartments of the caudate nucleus. No significant atrophy, cell loss, or neurochemical alterations are present in the substantia nigra in 5-year-old HD sheep. In the caudate nucleus, there is a reduction in volume of the striosome compartment relative to the matrix compartment in 5-year-old HD sheep. Finally, this thesis provides preliminary evidence that intra-striatal injection of a gene-silencing construct targeting the human HD gene does not disrupt expression of substance P or the GABAAα1 receptor subunit, both central to the functioning of basal ganglia circuitry. This data builds on evidence from collaborators that gene-silencing therapy is safe and effective in this large animal model of HD. Overall, the studies presented in this thesis support the sheep as an early stage model of HD and provide a glimpse at the future of research into gene-silencing therapy as an effective and meaningful therapy for HD.