Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress

Abstract Lysosomal clearance of proteotoxic stressors through autophagy is an essential process underlying cellular homeostasis. Its failure can lead to cell death 1,2 , by initiating apoptotic pathways 3–11 . However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and different cell death types may also be involved 12–14 . Here, we identify karyoptosis as a previously unknown form of non-apoptotic cell death. We report that karyoptosis is induced by lysosomal autophagic clearance impairment and proteotoxic stress; develops through nuclear degeneration; shares features with cellular senescence and is regulated by the p38a signalling pathway through direct phosphorylation of the nuclear lamina protein LaminB1. We further demonstrate that karyoptosis affects neurons in in-vitro and in-vivo 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, suggesting a common pathological signature. Together these findings establish a novel form of cell death directly linked to proteotoxic stress and cellular senescence that is associated with neurodegeneration. Finally, this mechanism provides new therapeutic opportunities in age-related neurodegenerative diseases.