Influence of species differences on the neuropathology of transgenic Huntington's disease animal models

Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets. Huntington's disease is a well-characterized neurodegenerative disorder that is caused by expansion of a CAG repeat, which results in expansion of a polyglutamine tract in the N-terminal region of huntingtin (HTT). Similar CAG/glutamine expansions are also found to cause eight other neurodegenerative diseases that affect distinct brain regions in an age-dependent manner. Identification of this CAG/glutamine expansion has led to the generation of a variety of transgenic animal models. Of these different animal models, transgenic mice have been investigated extensively, and they show similar neuropathology and phenotypes as seen in their respective diseases. The common pathological hallmark of age-dependent neurodegeneration is the formation of aggregates or inclusions consisting of misfolded proteins in the affected brain regions; however, overt or striking neurodegeneration and apoptosis have not been reported in most transgenic mouse models for age-dependent diseases, including HD. By comparing the neuropathology of transgenic HD mouse, pig, and monkey models, we found that mutant HTT is more toxic to larger animals than mice, and larger animals also show neuropathology that has not been uncovered by transgenic mouse models. This review will discuss the importance of transgenic large animal models for analyzing the pathogenesis of neurodegenerative diseases and developing effective treatments.