Basal Ganglia Functions in Huntington's Disease: Genetic Mouse Models

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DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative affliction caused by a genetic mutation that is transmitted in an autosomal dominant manner. Inheritance of the mutation is fatal. The symptoms of HD emerge in mid-life and include involuntary movement, psychiatric disturbance and cognitive impairment. The most severely affected areas of the brain are the cerebral cortex and the subcortical nuclei of the basal ganglia, in particular the caudate/putamen. There currently is no satisfactory therapy for the disease and the hope for a cure remains distant despite the fact that the gene affected in HD and the nature of the mutation have been known for nearly 15 years. The disease is caused by inheritance of an expanded region of CAG repeats in exon 1 of the gene coding for a ubiquitous protein of poorly understood function known as huntingtin. An expanded polyglutamine stretch near the N- terminus of the huntingtin protein results from the HD mutation. The number of glutamine repeats correlates with the age of onset and severity of HD although the molecular mechanisms mediating the neurotoxicity of the mutation remain unknown. During the past decade, knowledge of the molecular genetics of HD has led to exciting advances in the creation of genetically modified mouse models of HD. We propose to utilize two of these models (R6/2, YAC128) to conduct a systems-level analysis of the impact of the HD mutation on basal ganglia function in vivo with particular emphasis on the time-course of changes. This focus on circuit-level alterations of function in a neurodegenerative basal ganglia disease is inspired in part by analogous reasoning, i.e. the development of effective symptomatic treatments for Parkinson's disease, in which the primary pathology of nigrostriatal dopamine (DA) cell loss is known but the molecular basis of the neurotoxicity remains obscure. Dysfunction in basal ganglia DA pathways is also indicated in both human and mouse model studies of HD. We will analyze, in vivo, the status of the nigrostriatal and mesocortical DA systems in mouse HD models using biochemical, anatomical and electrophysiological approaches. Physiological studies of other sites in the basal ganglia (globus pallidus, subthalamic nucleus) will reveal potential "downstream" alterations in the circuitry. We hypothesize that such a systems-level understanding, previously lacking, will hasten development of symptomatic treatments for this devastating disease. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) results from genetically programmed degeneration of brain cells in selective areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. HD has a frequency of 4 to 7 per 100,000 persons and is a familial disease, passed from parent to child through a mutation in the normal gene. Now that the gene has been located, investigators are continuing to study the HD gene with the goal of understanding how the mutation causes this devastating fatal disorder.