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Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease
H Ishiguro1, K Yamada, H Sawada
1Institute for Comprehensive Medical Science, Fujita Health University, Toyoake Aichi 470-1192, Japan.
Insights
This study developed a Huntington's disease (HD) mouse model to investigate CAG repeat instability. The model shows CAG repeat changes mirroring human HD, offering insights into disease mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the HD gene.
- Understanding the instability of these repeats is crucial for developing effective treatments.
Purpose of the Study:
- To create and characterize a mouse model that accurately reflects CAG repeat instability in Huntington's disease.
- To investigate the factors influencing CAG repeat instability, including age and mode of transmission.
Main Methods:
- Generation of a Huntington's disease mouse model with expanded CAG repeats (77 repeats) in the HD gene.
- Analysis of CAG repeat length changes (expansion and contraction) across generations and in different tissues.
- Assessment of glial fibrillary acidic protein (GFAP) expression in specific brain regions.
Main Results:
- Paternal transmission led to CAG repeat expansion, while maternal transmission resulted in contraction.
- CAG repeat instability increased with age and was pronounced in specific organs like the liver, kidney, stomach, and brain.
- Increased GFAP-positive cells were observed in key brain areas (SN, GP, St) without neuronal cell death, mirroring human HD pathology.
Conclusions:
- The developed HD mouse model exhibits CAG repeat instability and neuropathological features consistent with human Huntington's disease.
- This model serves as a valuable tool for studying the molecular mechanisms underlying CAG repeat instability in HD.
- The findings highlight the potential for this model to aid in the development of therapeutic strategies for Huntington's disease.
Abstract:
Huntington's disease (HD) is a neurodegenerative disorder characterized by the expansion of CAG repeats in exon 1 of the HD gene. To clarify the instability of expanded CAG repeats in HD patients, an HD model mouse has been generated by gene replacement with human exon 1 of the HD gene with expansion to 77 CAG repeats. Chimeric proteins composed of human mutated exon 1 and mouse huntingtin are expressed ubiquitously in brain and peripheral tissues. One or two CAG repeat expansion was found in litters from paternal transmission, whereas contraction of CAG repeat in litters was observed through maternal transmission. Elderly mice show greater CAG repeat instability than younger mice, and a unique case was observed of an expanded 97 CAG repeat mouse. Somatic CAG repeat instability is particularly pronounced in the liver, kidney, stomach, and brain but not in the cerebellum of 100-week-old mice. The same results of expanded CAG repeat instability as observed in this HD model mouse were confirmed in the human brain of HD patients. Glial fibrillary acidic protein (GFAP)-positive cells have been found to be increased in the substantia nigra (SN), globus pallidus (GP), and striatum (St) in the brains of 40-week-old affected mice, although without neuronal cell death. The CAG repeat instability and increase in GFAP-positive cells in this mouse model appear to mirror the abnormalities in HD patients. The HD model mouse may therefore have advantages for investigations of molecular mechanisms underlying instability of CAG repeats.