Abstract
Huntington’s disease (HD) is caused by an expansion of the trinucleotide poly (CAG) tract located in exon 1 of the huntingtin (Htt) gene leading to progressive neurodegeneration in selected brain regions, and associated functional impairments in motor, cognitive, and psychiatric domains. Since the discovery of the gene mutation that causes the disease, mouse models have been developed by different strategies. Recently, a new model, the zQ175 knock-in (KI) line, was developed in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. The behavioral phenotype was characterized across the independent laboratories and important features reminiscent of human HD are observed in zQ175 mice. In the current study, we characterized the zQ175 model housed in an academic laboratory under reversed dark-light cycle, including motor function, in vivo longitudinal structural MRI imaging for brain volume, MRS for striatal metabolites, neuropathology, as well as a panel of key disease marker proteins in the striatum at different ages. Our results suggest that homozygous zQ175 mice exhibited significant brain atrophy before the motor deficits and brain metabolite changes. Altered striatal medium spiny neuronal marker, postsynaptic marker protein and complement component C1qC also characterized zQ175 mice. Our results confirmed that the zQ175 KI model is valuable in understanding of HD-like pathophysiology and evaluation of potential therapeutics. Our data also provide suggestions to select appropriate outcome measurements in preclinical studies using the zQ175 mice.
Highlights
Huntington’s disease (HD) is a progressive, inherited neurodegenerative disorder characterized by involuntary movements, cognitive impairment, and psychiatric manifestations
Our present study confirmed that the zQ175 mice have a much more robust phenotype than do the original HdhQ140 mice
Dysregulated selective neuronal marker proteins were evident in zQ175 mice
Summary
Huntington’s disease (HD) is a progressive, inherited neurodegenerative disorder characterized by involuntary movements, cognitive impairment, and psychiatric manifestations. Part of the problem has been that the model system we used to develop therapeutics does not fully reflect human genetics and disease phenotype, and most of the trials to date have attempted intervening at a time when the degenerative process is already far advanced, when it would be difficult for even the most effective therapy to demonstrate any benefit. People who will develop HD can be identified years before clinical onset, raising the possibility of initiating therapy in the prodromal period to delay or prevent disease onset. In order to predict the effectiveness of disease-modifying therapies and prepare candidate treatment for clinical trials, appropriate animal models and molecular markers that reflect neuronal dysfunction have become of paramount importance
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