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

Giel Korsten; Miriam Osinga; Robin A. Pelle; Albert K. Serweta; Baukje Hoogenberg; Harm H. Kampinga; Lukas C. Kapitein

doi:10.1083/jcb.202307142

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

Giel Korsten, Miriam Osinga, Robin A. Pelle, Albert K. Serweta, Baukje Hoogenberg, Harm H. Kampinga, Lukas C. Kapitein^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	e202307142
Number of pages	19
Journal	The Journal of cell biology
Volume	223
Issue number	11
DOIs	https://doi.org/10.1083/jcb.202307142
Publication status	Published - 4 Nov 2024

Bibliographical note

Publisher Copyright:
© 2024 Korsten et al.

Funding

We thank Martin Hetzer (ISTA, Klosterneuburg, Austria) for the gift of U2OS-RFP-NLS cells, Fulvio Reggiori, and Anna Akhmanova for discussions and advice, Anne Janssen for early observations of nuclear ruptures in cells with aggregates, Hugo Damstra for help with expansion microscopy, and Klara Jansen for advice regarding primary neuron culture. Akhmanova for discussions and advice, Anne Janssen for early observations of nuclear ruptures in cells with aggregates, HugoDamstra for help with expansion microscopy, and Klara Jansenfor advice regarding primary neuron culture.This research was supported by the European Research Council (ERC Consolidator Grant 819219 to L.C. Kapitein) and the Dutch Research Council (NWO, ZonMW 91217002 to H.H.Kampinga and L.C. Kapitein). DAS:All data underlying the figures are available via FigShare: https://figshare.com/collections/Nuclear_poly-glutamine_aggregates_rupture_the_nuclear_envelope_and_hinder_its_repair/7345940. Plasmids are available from L.C. Kapitein upon request.

Funders	Funder number
European Research Council (ERC Consolidator Grant)	819219
Dutch Research Council (NWO)

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abstract = "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.",

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AU - Pelle, Robin A.

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AU - Kampinga, Harm H.

AU - Kapitein, Lukas C.

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AB - 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.

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

Abstract

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