The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Abstract

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

“…Strain R6/2 is the product of strong expression of a transgene containing human mHTT exon 1 and its promoter (21). It has been widely used in the assessment of potential therapeutic interventions for HD (22,23). We found that D2GFP expression in the MSNs of R6/2 showed significant differences from the values for wild-type littermates at the earliest age we evaluated, 4.5-5 wk of age.…”

Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice

“…R6/2 mice are one of the most widely used models of HD because they show highly reproducible early-onset symptoms, allowing the use of fewer animals (38). Although R6/2 mice have very long CAG repeats (range: 115-160 repeats), which are rarely found in patients (typically in the range of 42-45 repeats), they are nonetheless ideal to assay acute phenotypic reversal at the molecular, histological, and early-symptom levels (39). Therefore, R6/2 mice were stereotaxically injected at 4 wk of age with AAV2/1-expressing ZF11xHunt-Kox-1.…”

Hippocampal Neurogenesis in Neurodegenerative Movement Disorders

“…In particular, data discrepancies from different studies addressing cell proliferation and cell survival may be attributable to differences between markers used for labeling cell proliferation (endogenous markers, such as Ki-67 and PCNA vs. exogenous labeling of proliferating cells with BrdU), as well as BrdU administration protocols for survival studies, quantifi cation methods for labeled cells, and various mouse colonies. Nevertheless, R6 mice have been intensively used in the evaluation of potential therapeutic strategies to ameliorate disease progression (review in Gil and Rego 2009 ).…”