Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.

Overview

1. Department of Basic and Clinical Neuroscience, King’s College London,London, UK
2. UK Dementia Research Institute at King’s College London,London, UK
3. Guy’s & St. Thomas’ Hospital NHS Foundation Trust,London, UK
4. Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille,Lille, France
5. College of Pharmacy, The Catholic University of Korea,Seoul, Republic of Korea
6. Centre for Inflammation Biology and Cancer Immunology, King’s College London,London, UK
7. Randall Division of Cell and Molecular Biophysics, King’s College London,London, UK

Abstract

Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer’s disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• zenodo:18772707, at Zenodo; found in the text, “Nuclear degeneration is caused by proteotoxic…”
• zenodo:18806148, at Zenodo; found in the text, “Nuclear degeneration is caused by proteotoxic…”
• zenodo:19220863, at Zenodo; found in the text, “Inhibition of autophagic lysosomal clearance…”
• zenodo:19221077, at Zenodo; found in the text, “Inhibition of autophagic lysosomal clearance…”
• zenodo:19348450, at Zenodo; found in the text, “The p38 mitogen activated kinase pathway…”
• zenodo:19349021, at Zenodo; found in the text, “The p38 mitogen activated kinase pathway…”
• zenodo:19353588, at Zenodo; found in the text, “Neurons undergo karyoptosis in in vitro and in…”
• zenodo:19709429, at Zenodo; found in the text, “The p38 mitogen activated kinase pathway…”
• zenodo:19734917, at Zenodo; found in the text, “Nuclear degeneration is caused by proteotoxic…”
• zenodo:19743163, at Zenodo; found in the text, “Nuclear degeneration is caused by proteotoxic…”
• zenodo:19768610, at Zenodo; found in the text, “Karyoptosis hallmarks are present in…”
• zenodo:20274655, at Zenodo; found in the text, “Neurons undergo karyoptosis in in vitro and in…”

Data availability

All proteomics data are available via ProteomeXchange with identifier PXD074564. Source data for other experiments are either provided with this paper in Supplementary files or deposited on Zenodo (see figure legends for details). Additional data, materials and details are available upon request. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 19 authors, 3 keywords, 14 MeSH terms, 2 funders, 68 references.

Cite

This paper

Casterton, R., Martinez-Cotrina, A., Barnard, J., Wycherley, E., Hu, Y., Anderson, R., Janel, S., Byun, J., Houghton, O., Solomon, D. A., Alcalde, J., Lafont, F., Ruepp, M.-D., Hirth, F., Tummers, B., Cho, Y.-Y., De Nicola, G., Mizielinska, S., & Fanto, M. (2026). Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress. Nature communications, 17(1), 5135. https://doi.org/10.1038/s41467-026-73802-w

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