Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair.

Autor:	Korsten G; Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands., Osinga M; Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands., Pelle RA; Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands., Serweta AK; Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands., Hoogenberg B; Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands., Kampinga HH; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands., Kapitein LC; Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands.; Centre for Living Technologies, Alliance TU/e, WUR, UU, UMC Utrecht University, Utrecht, Netherlands.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2024 Nov 04; Vol. 223 (11). Date of Electronic Publication: 2024 Aug 16.
DOI:	10.1083/jcb.202307142
Abstrakt:	Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases. (© 2024 Korsten et al.)
Databáze:	MEDLINE
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