ABSTRACT
Variability and modification of the symptoms of Huntington's disease (HD) are commonly observed in both patient populations and animal models of the disease. Utilizing a stable line of the R6/2 HD mouse model, the present study investigated the role of genetic background in the onset and severity of HD symptoms in a transgenic mouse. R6/2 congenic C57BL/6J and C57BL/6J×DBA/2J F1 (B6D2F1) mice were evaluated for survival and a number of behavioral phenotypes. This study reports that the presence of the DBA/2J allele results in amelioration or exacerbation of several HD-like phenotypes characteristic of the R6/2 mouse model and indicates the presence of dominant genetic modifiers of HD symptoms. This study is the first step in identifying genes that confer natural genetic variation and modify the HD symptoms. This identification may lead to novel targets for treatment and help elucidate the molecular mechanisms of HD pathogenesis.
Subject(s)
Behavior , Huntington Disease/genetics , Animals , Disease Models, Animal , Female , Humans , Huntington Disease/pathology , Huntington Disease/physiopathology , Huntington Disease/psychology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Motor ActivityABSTRACT
Huntington's disease (HD) is caused by the expansion of the polyglutamine tract expressed in the huntingtin protein. Data from patients show a strong negative correlation between CAG repeat size and age of disease onset. Recent studies in mixed background C57×CBA R6/2 mice suggest the inverse correlation observed in the human disease may not be replicated in some animal models of HD. To further clarify the relationship between repeat length and age of onset, congenic C57BL6/J R6/2 transgenic mice expressing 110, 260 or 310 CAG were tested in a comprehensive behavioral battery at multiple ages. Data confirmed the findings of earlier studies and indicate that on a pure C57BL6/J genetic background, R6/2 mice with larger repeats exhibit a delay in phenotypic onset with increasing polyglutamine size (6 weeks in 110 CAG and 17 weeks in 310 CAG mice). Further analysis confirmed a decrease in transgene transcript expression in 310 CAG mice as well as differential aggregated protein localization in association with repeat length. Mice expressing 110 CAG developed aggregates that localized almost exclusively to the nucleus of neuronal cells in the striatum and cortex. In contrast, tissue from 310 CAG mice exhibited predominantly extranuclear inclusions. Novel mutant protein analysis obtained using time-resolved fluorescence resonance energy transfer (FRET) revealed that soluble protein levels decreased with disease onset in R6/2 mice while aggregated protein levels increased. We believe that these data suggest a role for aggregation and inclusion localization in HD pathogenesis and propose a mechanism for the age of onset delay observed in R6/2 mice.
Subject(s)
Huntington Disease/genetics , Huntington Disease/physiopathology , Nerve Tissue Proteins/physiology , Neurons/metabolism , Proteins/metabolism , Age of Onset , Animals , Brain/metabolism , Disease Models, Animal , Fear/physiology , Humans , Huntingtin Protein , Male , Mice , Mice, Transgenic , Motor Activity/physiology , Motor Skills/physiology , Mutation , Nerve Tissue Proteins/genetics , Peptides/genetics , Phenotype , Sensory Gating/physiology , Trinucleotide Repeat Expansion/genetics , Trinucleotide Repeat Expansion/physiologyABSTRACT
In the present study we report on the use of speed congenics to generate a C57BL/6J congenic line of HD-model R6/2 mice carrying 110 CAG repeats, which uniquely exhibits minimal intergenerational instability. We also report the first identification of the R6/2 transgene insertion site. The relatively stable line of 110 CAG R6/2 mice was characterized for the onset of behavioral impairments in motor, cognitive and psychiatric-related phenotypes as well as the progression of disease-related impairments from 4 to 10 weeks of age. 110Q mice exhibited many of the phenotypes commonly associated with the R6/2 model including reduced activity and impairments in rotarod performance. The onset of many of the phenotypes occurred around 6 weeks and was progressive across age. In addition, some phenotypes were observed in mice as early as 4 weeks of age. The present study also reports the onset and progression of changes in several molecular phenotypes in the novel R6/2 mice and the association of these changes with behavioral symptom onset and progression. Data from TR-FRET suggest an association of mutant protein state changes (soluble versus aggregated) in disease onset and progression.
