Question

In detail explain how the R6/2 mouse was constructed and designed? What are the limitations?

Answer 1

R6/2 MOUSE

The transgenic R6/2 mouse is the most commonly used animal model of Huntington’s disease. The R6/2 mouse contains N-terminally truncated mutant Htt (mHtt) with CAG repeat expansion (~125 repeats) within the huntingtin gene exon 1. This model develops HD-like symptoms, including decreased body weight as well as motor and cognitive deficits, starting as early as 6-8 weeks of age. Survival is followed until 25 weeks of age.

Charles River conducted contract studies in transgenic R6/2 mice to test the efficacy of novel therapeutics for treating Huntington’s disease (HD).

These transgenic mice display a progressive neurological phenotype that mimics many of the features of Huntington Disease (HD) in humans, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components, including unusual vocalization. Frequent urination and loss of body weight and muscle bulk occurs through the course of the disease. Neurological developments include Neuronal Intranuclear Inclusions, which contain both the huntingtin and ubiquitin proteins. Onset of HD symptoms occurs between 15 and 21 weeks of age.

The R6/2 transgenic mouse lines express a transgene encoding the 5' end of human HTT with different lengths of CAG repeat expansions. The CAG repeat number is subject to germline and somatic instability, and may expand or contract. The phenotype of R6/2 animals varies greatly as a function of CAG repeat size and, similar to what is observed in humans, R6/2 transgenic mice may exhibit higher incidence of CAG repeat expansion when the transgene is transmitted via paternal inheritance. Interestingly, the phenotype relationship is not linear for R6/2 mice, nor does a large CAG repeat number necessarily lead to an earlier onset and more severe phenotype. Genetic background may also lead to variations in disease severity/progression.

First there was performed a systems-wide exploration of protein changes in four brain regions (striatum, cortex, hippocampus, and midbrain) from 12-week-old transgenic R6/2 mice. Notably, R6/2 mice recapitulate several HD phenotypes, including movement disturbances, muscle wasting, and premature death at about 14 to 16 weeks and, therefore, constitute a commonly used HD model system.

Limitations

The absence of a full-length mutant HTT protein and the extremely rapid progression of disease.This leads to development of many other models.