The massive loss of neurons in this region, normally responsible (among many things) for facilitation of volitional movement, is believed to lead to the characteristic motor dysfunctions of HD, such as uncontrolled limb and trunk movements, difficulty Olaparib chemical structure maintaining gaze, and general lack of balance and coordination ( Bates et al., 2002). Neuronal loss or dysfunction also leads to cognitive problems, behavioral abnormalities, and psychological dysfunction, some of which are reported before motor abnormalities are noticeable. Importantly, some patients present with a more rigid,

Parkinsonian form of the disease, typical when age of onset is under 20 (so called juvenile onset cases). These children generally have large repeats, up to 120 for a 3-year-old patient ( Cannella et al., 2004). The distinctive features of juvenile HD cause many investigators to think of it as a discrete subform of HD that may involve distinctive pathological processes. Expanded poly(CAG) HTT leads to production

of huntingtin protein with an equally expanded polyglutamine (polyQ) stretch near the N terminus. Despite a lack of consensus on the function of wild-type huntingtin (wtHTT), it is well established Androgen Receptor animal study through studies of human tissue, cellular models, and animal models that mutant polyQ huntingtin (mHTT) exerts a gain of toxic function through aberrant protein-protein interactions. Inclusions containing mHTT, wtHTT, ubiquitin, and many cellular proteins ( Hoffner and Djian, 2002) are seen in patients and animal models. These aggregates are not necessarily toxic, but they are commonly observed wherever mHTT is expressed. That the same aggregates and cellular toxicity observed in humans are also seen in many models, with drastically different time scales (from days in tissue culture to decades in human HD), accentuates the importance of expression levels and protein context in cellular pathology. This is particularly evident in the wide variety of phenotypic

progression seen in the many mouse models of HD, which is the subject of this review. A mutant HD gene is present in the body of an individual from conception. The potential for beneficial isothipendyl therapeutic intervention is therefore present throughout the life of an affected individual. However, the physiological consequences of the presence of the HD mutation differ as life progresses. A key issue in utilizing a mouse model to test therapeutic intervention for HD is to assess which stage of disease a model corresponds to at any given point in time. Some strains display neuropathology from birth and early mortality, while others progress so slowly that visible phenotypes are not seen until the mice are very old, and do not present with morbidity. The age of onset of a number of frequently utilized behavioral and biological measures of pathology for HD mouse models are summarized in Figure 1. The first transgenic model of HD in mice was developed in 1996 (Mangiarini et al.