Mouse Models of Mental Illness and Neurological Disease: Huntington s Disease

Publisher Summary Huntington's disease (HD) is an autosomal dominant, genetic disorder that causes progressive degeneration in the central nervous system (CNS). Patients exhibit inexorable decline in motor control and cognitive function, in addition to psychiatric disturbances. The disease, which affects up to 1 in 10,000 people worldwide, is caused by the expansion of a trinucleotide cytosine-adenineguanine (CAG) repeat within exon 1 of the HD gene. Disease onset is usually in midlife and progresses towards death within 20 years. Although some symptoms may be treated, there are currently no effective disease-modifying agents. Animal models of HD have provided insights into the pathogenic mechanisms underlying the disease and have been used widely for preclinical assessment of therapeutic strategies. In HD, several mechanisms are likely implicated in causing neurodegeneration, including metabolic compromise, oxidative stress, excitotoxicity, and alterations in gene expression. Models of HD in vitro and in vivo have made a significant contribution to the current understanding of HD pathogenesis. Animal models of HD may be broadly divided into two types: those generated by neurotoxic chemical lesions of the striatum and those generated by expression of fragments or full-length mutant htt. Prior to the identification of the underlying genetic mutation in HD, animal models that mimic striatal neuronal cell loss were generated by excitotoxic lesioning of the striatum or metabolic impairment via mitochondrial disruption. Developments in recombinant virus vector technology have facilitated the generation of animal models of HD based on transfer of mutant htt expression constructs into the somatic brain cells of experimental animals. A main purpose for generating mouse models of diseases is to provide a tool for preclinical drug testing of potential therapies. There is currently no treatment that delays onset, slows progression, or reverses the course of HD.