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Transgenic models of Huntington's disease
K Sathasivam1, C Hobbs, L Mangiarini
1GKT Medical and Dental School, King's College, Guy's Hospital, London, UK.
Summary
Huntington's disease mouse models show inclusions in skeletal muscle, offering new insights into muscle atrophy and potential drug targets for this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder.
- It is caused by a CAG-polyglutamine repeat expansion in the HD gene.
- R6 lines of transgenic mice carrying expanded CAG repeats serve as a disease model.
Purpose of the Study:
- Investigate skeletal muscle atrophy in R6 mouse models.
- Gain insights into muscle bulk loss observed in HD patients.
- Analyze the consequences of protein aggregate formation in skeletal muscle, paralleling brain studies.
- Evaluate skeletal muscle inclusions as a potential biomarker for therapeutic interventions.
Main Methods:
- Generation of transgenic mice (R6 lines) with expanded CAG repeats.
- Phenotypic analysis of neurological and physical symptoms.
- Histopathological examination of brain and skeletal muscle tissues.
- Identification and characterization of protein inclusions.
Main Results:
- Transgenic mice exhibit progressive neurological symptoms and weight loss similar to HD patients.
- Neuronal inclusions, a hallmark of polyglutamine diseases, are present before symptoms and neuronal death.
- Protein inclusions were identified in the skeletal muscle of R6 mice.
- Skeletal muscle atrophy was observed in the R6 mouse model.
Conclusions:
- Skeletal muscle atrophy in HD mouse models may reflect muscle bulk loss in patients.
- Inclusions in skeletal muscle offer a potential target for monitoring therapeutic efficacy in vivo.
- This study highlights the broader impact of polyglutamine repeat expansions beyond the central nervous system.