Large Animal Models of Huntington's Disease.

Huntington's disease is caused by the expansion of a polyglutamine repeat (>37 glutamines) in the disease protein huntingtin, which results in preferential neuronal loss in distinct brain regions. Mutant huntingtin causes late-onset neurological symptoms in patients in middle life, though the expression of mutant huntingtin is ubiquitous from early life. Thus, it is important to understand why mutant huntingtin selectively causes neuronal loss in an age-dependent manner. Transgenic animal models have been essential tools for uncovering the pathogenesis and therapeutic targets of neurodegenerative diseases. Genetic mouse models have been investigated extensively and have revealed the common pathological hallmark of age-dependent formation of aggregates or inclusions consisting of misfolded proteins. However, most genetic mouse models lack striking neurodegeneration that has been found in patient brains. Since there are considerable species differences between small and large animals, large animal models of Huntington's disease may allow one to identify the pathological features that are more similar to those in patients and also help uncover more effective therapeutic targets. This chapter will focus on the important findings from large animal models of Huntington's disease and discusses the use of large animal models to investigate the pathogenesis of Huntington's disease and develop new therapeutic strategies.