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<p>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 <i>post-mortem</i> 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.</p>

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Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Rebecca Casterton,
  • Aitana Martinez-Cotrina,
  • Jodi Barnard,
  • Eleanor Wycherley,
  • Yanling Hu,
  • Rhys Anderson,
  • Sebastien Janel,
  • Jiin Byun,
  • Olivia Houghton,
  • Daniel A. Solomon,
  • Juan Alcalde,
  • Frank Lafont,
  • Marc-David Ruepp,
  • Frank Hirth,
  • Bart Tummers,
  • Yong-Yeon Cho,
  • Gian De Nicola,
  • Sarah Mizielinska,
  • Manolis Fanto

摘要

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.