Cellular Defects in ataxia-telangiectasia
Author(s)
Dunner, Emily
Newman, Judith
Watters, Dianne
Year published
2007
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Dunner EM, Newman JV and Watters DJ. School of Biomolecular and Physical Sciences and The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland, 4111, Australia. Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disease characterised by oxidative stress and cancer predisposition. Extensive research has characterised the DNA damage response role for nuclear ATM (ataxia-telangiectasia-mutated), the protein defective in A-T, however very little is known about the role of cytoplasmic ATM. In this study, novel mechanisms contributing to disease progression in A-T were ...
View more >Dunner EM, Newman JV and Watters DJ. School of Biomolecular and Physical Sciences and The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland, 4111, Australia. Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disease characterised by oxidative stress and cancer predisposition. Extensive research has characterised the DNA damage response role for nuclear ATM (ataxia-telangiectasia-mutated), the protein defective in A-T, however very little is known about the role of cytoplasmic ATM. In this study, novel mechanisms contributing to disease progression in A-T were investigated. We examined the endosomal recycling of membrane receptors for epidermal growth factor (EGF) and transferrin in control and A-T fibroblasts, as well as the cellular distribution of cholesterol and lipid droplets in control and A-T fibroblasts, and in astrocytes from wild-type and A-T mice. Transferrin and EGF remained localised to the perinuclear region in A-T fibroblasts, indicating defective recycling in A-T. Immunofluorescence studies showed partial colocalisation of transferrin with recycling endosome markers. Other cellular anomalies observed included increased intracellular cholesterol. Using the unesterified cholesterol-binding fluorescence antibiotic, filipin, a bright punctate intracellular staining pattern in cytoplasmic vesicles was revealed in the perinuclear region of A-T fibroblasts while minimal internal staining was seen in controls. Nile red labelling for lipid droplets indicated increased lipid droplets in A-T fibroblasts compared to controls. This was also observed in A-T astrocytes relative to wild-type. Treatment of control fibroblasts with hydrogen peroxide led to punctate cytoplasmic filipin staining and increased lipid droplets in the treated fibroblasts similar to that seen in A-T fibroblasts, suggesting that the increased lipid droplets and abnormal cholesterol distribution may be due to oxidative stress. We have also observed defective sphingolipid trafficking and mitochondrial abnormalities in A-T cells. All of these features could contribute to neurodegeneration in A-T.
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View more >Dunner EM, Newman JV and Watters DJ. School of Biomolecular and Physical Sciences and The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland, 4111, Australia. Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disease characterised by oxidative stress and cancer predisposition. Extensive research has characterised the DNA damage response role for nuclear ATM (ataxia-telangiectasia-mutated), the protein defective in A-T, however very little is known about the role of cytoplasmic ATM. In this study, novel mechanisms contributing to disease progression in A-T were investigated. We examined the endosomal recycling of membrane receptors for epidermal growth factor (EGF) and transferrin in control and A-T fibroblasts, as well as the cellular distribution of cholesterol and lipid droplets in control and A-T fibroblasts, and in astrocytes from wild-type and A-T mice. Transferrin and EGF remained localised to the perinuclear region in A-T fibroblasts, indicating defective recycling in A-T. Immunofluorescence studies showed partial colocalisation of transferrin with recycling endosome markers. Other cellular anomalies observed included increased intracellular cholesterol. Using the unesterified cholesterol-binding fluorescence antibiotic, filipin, a bright punctate intracellular staining pattern in cytoplasmic vesicles was revealed in the perinuclear region of A-T fibroblasts while minimal internal staining was seen in controls. Nile red labelling for lipid droplets indicated increased lipid droplets in A-T fibroblasts compared to controls. This was also observed in A-T astrocytes relative to wild-type. Treatment of control fibroblasts with hydrogen peroxide led to punctate cytoplasmic filipin staining and increased lipid droplets in the treated fibroblasts similar to that seen in A-T fibroblasts, suggesting that the increased lipid droplets and abnormal cholesterol distribution may be due to oxidative stress. We have also observed defective sphingolipid trafficking and mitochondrial abnormalities in A-T cells. All of these features could contribute to neurodegeneration in A-T.
View less >
Conference Title
Proceedings of the 102nd annual meeting of the Anatomische Gesellschaft