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Light and electron microscopic characterization of the evolution of cellular pathology in the R6/1 Huntington's
Zubeyde Bayram-Weston1, Lesley Jones, Stephen B Dunnett
1School of Bioscience, Cardiff University, Wales, UK. Bayram-WestonZ@cardiff.ac.uk
Insights
Huntington's disease mouse models show widespread protein inclusions in neurons, with early striatal volume loss and cell death. These inclusions vary in location and development over time.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder.
- It is caused by CAG repeat expansion in the Huntingtin (Htt) gene.
- HD patient brains exhibit nuclear htt aggregates and inclusions.
Purpose of the Study:
- To characterize neuronal pathology in the R6/1 transgenic mouse model of HD.
- To detail the formation and distribution of Huntingtin (Htt) protein inclusions.
Main Methods:
- Utilized the R6/1 transgenic mouse model.
- Examined brains from 2-11 month old mice using immunohistochemistry (S830 antibody) and electron microscopy.
- Assessed glial fibrillary acid protein (GFAP) immunoreactivity.
Main Results:
- R6/1 mice developed intra-nuclear and extra-nuclear inclusions by 2-11 months.
- Inclusions were widespread, with irregular distribution in striatum, cortex, and hippocampus.
- Ventral striatum showed more inclusions than dorsal striatum.
- Early signs of pathology included cytoplasmic abnormalities and vacuolization by 1.5 months.
- Striatal volume loss and cell loss were observed in 2-month-old R6/1 mice.
- Increased GFAP immunoreactivity in the cortex at 4-6 months.
Conclusions:
- The R6/1 mouse model exhibits significant neuronal pathology relevant to Huntington's disease.
- Neuronal intranuclear inclusions (NIIs) show considerable temporal and spatial variation.
- Early cellular changes and striatal degeneration occur before widespread NII detection.
Abstract:
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of CAG repeats in the Htt gene. Examination of the post-mortem brains of HD patients shows the presence of diffuse nuclear htt immunoreactivity and intra-nuclear inclusions. The aim of this study was to produce a detailed characterization of the neuronal pathology in the R6/1 transgenic mouse model. The R6/1 carrier mice demonstrate intra-nuclear and extra-nuclear inclusions with the S830 htt antibody at 2-11 months of age. The distribution pattern of neuronal intra-nuclear inclusions (NIIs) was irregular in several brain regions including the striatum, cortex and hippocampus. A greater number of NIIs were found in the ventral striatum than in the dorsal striatum. In the globus pallidus, cerebellum and thalamus the pattern of inclusion formation was relatively consistent over time. At 4 and 6 months of age, the R6/1 mice showed increased glial fibrillary acid protein (GFAP) immunoreactivity in the cortex compared to their wildtype littermates, yet no difference was found in the striatum. Analysis by electron microscopy found that neurons from the R6/1 carriers contained a densely packed cytoplasm at 1.5 months of age, with some neurons displaying structural abnormalities including vacuolization and nuclear membrane folding. No NIIs were detected at this age, but by 7 months of age, NIIs were present with severe cellular vacuolization. The present study indicates that a decrease in striatal volume with cell loss is present in young (2 months) R6/1 mice, and the distribution of NIIs is robust and widespread, with considerably temporal and spatial variation in NII development between mice.
