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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.
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.
multiple stress models support the phenotype, but distinctness and death endpoints remain operationally limited
karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation.
biochemical and phospho-mutant evidence converge, although some reported rescue comparisons are non-significant
karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology.
rodent-neuron and fly DPR models converge, despite an incompatible statistic in one neuronal panel
we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients.
cross-sectional morphology identifies compatible features but cannot establish the underlying death process
karyoptosis appears to be responsible for a remarkable extra 18–20% of cell degeneration in FTLD or AD.
cross-sectional cell clustering cannot identify a causal share of degeneration and ignores case-level dependence
Derived from the full evaluation — not a separate score.
Strengths
The study combines p38 inhibition, p38 RNAi, an in vitro kinase assay, and non-phosphorylatable LaminB1/LaminB mutants. Rescue of fly survival and lamina morphology gives the proposed pathway functional support beyond a single reagent.
↳ Results, Figs. 4–6
The proposed phenotype is examined in neuroblastoma cells, rat primary neurons, Drosophila, engineered human iPSC-derived neurons, and post-mortem cortex. This broadens the contribution beyond one model or assay.
↳ Results, Figs. 1–8
The paper evaluates apoptosis, necroptosis, ferroptosis, parthanatos, and senescence-associated markers rather than defining karyoptosis solely by morphology. It also discusses CREB3-associated karyoptosis and linker-cell death as related precedents.
↳ Results, Fig. 3 and Supplementary Figs. 2–4; Discussion, paragraph 1
Limitations
Several imaging tests treat hundreds of cells as inferential observations, while the post-mortem χ² analysis treats 763 cells from 20 cases as independent. These analyses do not account for clustering within wells, experiments, flies, or human cases.
↳ Figs. 1b,e,h, 4b–f, and 8
Fig. 6c contains an incompatible F/p pair, while the direct rescue comparisons in Figs. 4f and 6k are non-significant despite stronger narrative claims. These discrepancies create a material Internal Coherence concern.
↳ Figs. 4f and 6c,k legends; corresponding Results sections
Cross-sectional morphology and k-means clusters identify cells with compatible features but cannot show that karyoptosis caused their degeneration or quantify a causal 18–20% share. The case-level sampling structure is also absent from the inferential model.
↳ Results, Fig. 8 and final paragraph before Discussion
The multi-system design and convergent pharmacological, genetic, and biochemical interventions support a meaningful p38–LaminB1 mechanistic hypothesis. The principal score constraint is inferential: cell-level tests in Figs. 1 and 4 and the 763-cell post-mortem analysis in Fig. 8 do not account for their hierarchical sampling structures. The human-tissue data support identification of compatible morphological features, not a causal estimate that karyoptosis produces an additional 18–20% of degeneration. Statistical inconsistencies in Figs. 4 and 6 further reduce confidence in portions of the p38 and DPR evidence.
Nabu’s assessment, alongside the field’s view.
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Limited2.9
Confidence mediumThe study meaningfully extends prior work by connecting proteotoxic stress, LaminB1 destabilisation, p38 phosphorylation, and neuronal degeneration across cellular, fly, human-neuron, and post-mortem systems. Distinctness as a death mechanism and the quantitative human-disease attribution remain less secure than the mechanistic proposal.
“karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress”
The design uses orthogonal pharmacological and genetic perturbations, phospho-mutant rescue, and several model systems. Methodological Rigour is constrained by cell-level inference in central imaging panels, case-clustered post-mortem observations analysed as individual cells, and causal disease attribution from cross-sectional morphology.
The progression from induced stress through mechanism, disease models, and human tissue is readily followable. Categorical statements that p38 directly controls the process and that karyoptosis is responsible for an extra 18–20% of degeneration exceed the reported comparisons and observational design.
“karyoptosis appears to be responsible for a remarkable extra 18–20% of cell degeneration”
The paper engages apoptosis, regulated necrosis, senescence, CREB3-associated karyoptosis, and linker-cell death, and it identifies unresolved molecular and EV questions. It does not adequately trace cell non-independence and cross-sectional post-mortem morphology into the certainty of its quantitative disease-burden conclusion.
Concerns4 of 4 checks
Reported statistics and narrative interpretations are not fully coherent in several figures central to the p38 mechanism and disease-model claims. These are substantive reporting concerns rather than merely unavailable external verification.
Required human-tissue ethics approval and iPSC consent provenance are declared, human-tissue analysis is reported as blinded, and persistent data-repository identifiers are supplied. No text-grounded conduct concern was identified.
Flags: 2 declared / 5 total
69 references in manuscript 69 of 69 checkable references found in an index
No retraction notice found in Retraction Watch.
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Where this paper’s evidence sits on the path from initial observation to real-world use.
The mechanism is tested in cells, human iPSC-derived neurons, and Drosophila, including pharmacological and genetic rescue. No therapeutic intervention is evaluated in a mammalian neurodegeneration model or clinical setting.
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