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Repository DOI
Publication Date
2024-10-23
Type
doctoral thesis
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Abstract
Ataxia telangiectasia (A-T) is a cerebellar ataxia caused by mutations in the ATM gene, leading to the progressive loss of Purkinje cells, though the mechanisms underlying this cell death are still largely unknown. While ATM is mainly recognized as a DNA damage response protein, it also plays a crucial role in many other cellular processes. Recently, it has emerged as a regulator of mechanotransduction. Using immunofluorescence, Brillouin microscopy, and laser microdissection proteomics, we investigated how mechanical dysfunction contributes to the degeneration of Purkinje cells in A-T patients. We found that Purkinje cell nuclei exhibit unique mechanical and elastic properties, making them especially vulnerable to chromatin hypermethylation and nuclear envelope invaginations in the absence of ATM. Furthermore, laser-capture proteomics of Purkinje cells from A-T patients revealed dysregulated mechanotransduction and chromatin remodeling pathways. Finally, we present in vitro evidence that promoting chromatin relaxation through various inhibitor treatments can rescue the nuclear shape defects in A-T Purkinje cells. Our findings suggest that mechanical stress in A-T Purkinje cells may contribute to their degeneration in Ataxia telangiectasia and highlight innovative therapeutic strategies targeting nuclear mechano-dysfunction in A-T patients.
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Publisher
University of Galway
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International