Temporal Phenotypic Changes in Huntington’s Disease Models for Preclinical Studies

Abstract

Background: Mouse models bearing genetic disease mutations are instrumental in the development of therapies for genetic disorders. Huntington’s disease (HD) is a late-onset lethal dominant genetic disorder due to a CAG repeat within exon 1 of the Huntingtin (Htt) gene. Several mice were developed to model HD through the expression of a transgenic fragment (exon 1 of the human HTT), the knock-in mutation of the CAG repeat in the context of the mouse Htt gene, or the full-length HTT human gene. The different mouse models present distinct onset, symptoms, and progression of the disease. Objective: The objective of this study is to advise on the best behavioral tests to assess disease progression in three HD mouse models. Methods: We tested N171-82Q transgenic mice, zQ175 knock-in mice, and BACHD full-length mice in a comprehensive behavior test battery in early, mid-, and late disease stages. Results: We contrast and compare the models and the emerging phenotypes with the available literature. These results suggest the most effective behavioral tests and appropriate sample sizes to detect treatment efficacy in each model at the different ages. We provide options for early detection of motor deficits while minimizing testing time and training. Conclusion: This information will inform researchers in the HD field as to which mouse model, tests and sample sizes can accurately and sensitively detect treatment efficacy in preclinical HD research.

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

“…We next assessed Rpa2 protein levels in striatum and cerebellum of the zQ175 HD mouse model prior to disease onset (11 weeks), in mid-disease (48 weeks), and in late disease (82 weeks) 56 . Since mice contain a non-functional Rpa4 pseudogene, Rpa4 expression was not assessed.…”

Small Molecule Pytren-4QMn Metal Complex Slows down Huntington’s Disease Progression in Male zQ175 Transgenic Mice

“…Huntington's disease (HD) is a rare inherited neurodegenerative disorder with a prevalence rate of 5.7/100,000 in populations of European ancestry [1,2]. It is caused by an autosomal dominant mutation in the first exon of the huntingtin (HTT) gene, resulting in a more than fifty-fold increase in the number of HTT constitutive CAG trinucleotide repeats (CAG repeats) and the consequent translation of poly-glutamine (poly-Q) enlarged huntingtin proteins [3].…”