Neurological abnormalities in a knock-in mouse model of Huntington's disease

Abstract

Mice representing precise genetic replicas of Huntington's disease (HD) were made using gene targeting to replace the short CAG repeat of the mouse Huntington's disease gene homolog (HDH:) with CAG repeats within the length range found to cause HD in humans. Mice with alleles of approximately 150 units in length exhibit late-onset behavioral and neuroanatomic abnormalities consistent with HD. These symptoms include a motor task deficit, gait abnormalities, reactive gliosis and the formation of neuronal intranuclear inclusions predominating in the striatum. This model differs from previously described HDH: knock-ins by its method of construction, longer repeat length and more severe phenotype. To our knowledge, this is the first knock-in mouse model of HD to show increased glial fibrillary acidic protein immunoreactivity in the striatum, suggesting that these mice have neuronal injury similar to that found early in the course of HD. These mice will serve as useful reagents in experiments designed to reveal the molecular nature of neuronal dysfunction underlying HD.

Mouse models of Huntington's disease

“…A key differentiation among the HD knock-in mouse models reported to date, however, is whether the expanded CAG tract is inserted into an otherwise unaltered mouse Htt exon 1 or into a humanized exon 1 sequence. In the former case, the knock-in lines express a mutant form of mouse Htt (Lin et al, 2001;Sathasivam et al, 2013), but in the latter case the knock-in lines express a mutant Htt with a chimeric mouse-human HTT (Levine et al, 1999;Menalled et al, 2003;Shelbourne et al, 1999;Wheeler et al, 1999). Therefore, if preclinical strategies require the presence of a human HTT gene and protein sequence then the knock-in series of mice should not be used.…”

“…The second group is an allelic series of knock-in mice generated and created by Lin and Detloff at the University of Alabama, Birmingham (UAB) (Lin et al, 2001). These knock-in mice have expanded (CAG)nCAACAG tracts where N is 50, 100, 150, 200, 250, 315 and 365 in the mouse Htt exon 1 sequence (Heng et al, 2010b;Lin et al, 2001;Sathasivam et al, 2013).…”

“…These knock-in mice have expanded (CAG)nCAACAG tracts where N is 50, 100, 150, 200, 250, 315 and 365 in the mouse Htt exon 1 sequence (Heng et al, 2010b;Lin et al, 2001;Sathasivam et al, 2013). The 150 CAG-repeat line, denoted HdhQ150, is the most well studied of this series.…”

“…At later ages, however, they typically develop more robust behavioral abnormalities and huntingtin aggregate pathology (Brooks et al, 2012b;Brooks et al, 2012c;Brooks et al, 2006;Heng et al, 2010b;Hickey et al, 2008;Lin et al, 2001;Menalled et al, 2012b). Most of the knock-in lines have normal life spans, although the homozygous zQ175 and HdhQ150 mice reach end-stage disease at around 22-23.5 month of age and have shortened life spans (Menalled et al, 2012b;Woodman et al, 2007).…”

“…Second, it has been argued that heterozygous knock-ins, as stated above, better genocopy the majority of human HD patients, who typically carry a dominant, single HTT allele with expanded CAG repeats. Although homozygous mice typically do present with more robust phenotypes, particularly with respect to behavior, further comprehensive investigations have also uncovered phenotypes in heterozygous knock-in mice (Heikkinen et al, 2012;Heng et al, 2007;Lin et al, 2001;Menalled et al, 2012b;Rising et al, 2011). The key question is whether homozygous and heterozygous knock-in mouse models are equally valid in modeling HD.…”