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Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD
K Sathasivam1, B Woodman, A Mahal
1Division of Medical and Molecular Genetics, GKT School of Medicine, King's College London, UK.
Insights
Huntington's disease (HD) pathology progresses in non-central nervous system cells. Fibroblast lines from R6/2 mice and HD patients show multiple centrosomes, explaining cellular defects in this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a progressive neurodegenerative disorder.
- It is caused by a CAG/polyglutamine repeat expansion in the HTT gene.
- The R6/2 mouse model recapitulates key aspects of HD.
Purpose of the Study:
- To investigate the cellular pathology of Huntington's disease in non-central nervous system cells.
- To characterize cellular phenotypes in fibroblast lines from R6/2 mice and HD patients.
- To identify novel pathological mechanisms in Huntington's disease.
Main Methods:
- Establishment and culture of fibroblast lines from R6/2 mice at different ages (6, 9, and 12 weeks).
- Establishment and culture of fibroblast lines from a juvenile Huntington's disease patient.
- Microscopic analysis of cell morphology, nuclear aberrations, micronuclei, vacuoles, and centrosome number.
- Assessment of mitotic index, aneuploidy, and midbody persistence.
Main Results:
- Fibroblast lines could not be established from 12-week-old R6/2 mice, unlike younger mice.
- Fibroblasts from older R6/2 mice and HD patients exhibited dysmorphic cells with aberrant nuclear morphology, micronuclei, and large vacuoles.
- A high frequency of multiple centrosomes was observed in fibroblasts from both R6/2 mice and HD patients.
- These centrosome abnormalities correlated with reduced mitotic index, aneuploidy, and midbody persistence.
- Large insoluble polyglutamine aggregates were not detected in either cell type.
Conclusions:
- A novel progressive Huntington's disease pathology exists in non-central nervous system cells.
- Multiple centrosomes are a key feature of HD cellular pathology, potentially explaining observed phenotypes.
- Further investigation into these non-neuronal cells can provide insights into the cellular basis of Huntington's disease.
Abstract:
Huntington's disease (HD) is a progressive neurological disorder caused by a CAG/polyglutamine repeat expansion. We have previously generated the R6/2 mouse model that expresses exon 1 of the human HD gene containing CAG repeats in excess of 150. These mice develop a progressive neurological phenotype with a rapid onset and progression. We show here that it is impossible to establish fibroblast lines from these mice at 12 weeks of age, whilst this can be achieved without difficulty at 6 and 9 weeks. Cultures derived from mice at 12 weeks contained a high frequency of dysmorphic cells, including cells with an aberrant nuclear morphology and a high frequency of micronuclei and large vacuoles. All of these features were also present in a line derived from a juvenile HD patient. Fibroblast lines derived from R6/2 mice and from HD patients were found to have a high frequency of multiple centrosomes which could account for all of the observed phenotypes including a reduced mitotic index, high frequency of aneuploidy and persistence of the midbody. We were unable to detect large insoluble polyglutamine aggregates in either the mouse or human lines. We have identified a novel progressive HD pathology that occurs in cells of non-central nervous system origin. An investigation of the pathological consequences of the HD mutation in these cells will provide insight into cellular basis of the disease.
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