Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress
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.
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BibTeX
@article{casterton2026karyoptosis,
title = {{Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress}},
author = {Rebecca Casterton and Aitana Martinez-Cotrina and Jodi Barnard and Eleanor Wycherley and Yanling Hu and Rhys Anderson and Sebastien Janel and Jiin Byun and Olivia Houghton and Daniel Solomon and Juan Alcalde and Frank Lafont and Marc-David Ruepp and Frank Hirth and Bart Tummers and Yong-Yeon Cho and Gian de Nicola and Sarah Mizielinska and Manolis Fanto},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-73802-w},
url = {https://hal.science/hal-05764565v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress
AU - Rebecca Casterton
AU - Aitana Martinez-Cotrina
AU - Jodi Barnard
AU - Eleanor Wycherley
AU - Yanling Hu
AU - Rhys Anderson
AU - Sebastien Janel
AU - Jiin Byun
AU - Olivia Houghton
AU - Daniel Solomon
AU - Juan Alcalde
AU - Frank Lafont
AU - Marc-David Ruepp
AU - Frank Hirth
AU - Bart Tummers
AU - Yong-Yeon Cho
AU - Gian de Nicola
AU - Sarah Mizielinska
AU - Manolis Fanto
PY - 2026
DA - 2026/06/25
JO - Nature Communications
DO - 10.1038/s41467-026-73802-w
UR - https://hal.science/hal-05764565v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -