Disruption of nuclear envelope integrity as a possible initiating event in tauopathies

Prissette, Marine; Fury, Wen; Koss, Matthew; Racioppi, Claudia; Федорова, Д. В.; Dragileva, Ella; Clarke, Georgia; Pohl, Taylor; Dugan, John P.; Ahrens, Diana; Chiu, Joyce; Hunt, Charleen; Siao, Chia-Jen; Young, Tara M.; Bhowmick, Arijit; Rogulin, Vitaliy; Desclaux, Mathieu; Hayden, Eric Y.; Podgorski, Michael S.; Gao, Min; Macdonald, Lynn E.; Frendewey, David; Yancopouloš, George D.; Zambrowicz, Brian

doi:10.1016/j.celrep.2022.111249

Cited by 27 publications

(24 citation statements)

References 63 publications

(69 reference statements)

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“…4 and 6). This nding is consistent with earlier reports on human AD as well as the aberrant interaction between pathogenic tau and nuclear pore components [54][55][56][57][58]. Nuclear envelope disruption may also impair the structures that anchor heterochromatin and cause genomic injury [59].…”

Section: Discussionsupporting

confidence: 92%

Modeling Alzheimer’s disease in primary neurons reveals DNA damage response coupled with MAPK-DLK signaling in wild-type tau-induced neurodegeneration

Roy

Wang

et al. 2023

Preprint

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Background: Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. Methods: To model AD-relevant neurodegeneration driven by tau, we overexpressed wild-type human tau in primary mouse neurons and characterized the subsequent cellular and molecular changes. RNAseq profiling and functional investigation were performed as well. A direct comparison with a mutant human tau was conducted in detail. Results: We observed substantial axonal degeneration and cell death associated with wild-type tau, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. Conclusions: We have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between DNA damage response and the MAPK-DLK axis in the neuronal degenerative process.

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Section: Discussionsupporting

confidence: 92%

Modeling Alzheimer’s disease in primary neurons reveals DNA damage response coupled with MAPK-DLK signaling in wild-type tau-induced neurodegeneration

Roy

Wang

et al. 2023

Preprint

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“…Interestingly, anomalous invaginations of the nuclear envelope have been found in AD and FTLD-tau patients ( Paonessa et al, 2019 ; Kang et al, 2021 ), and tau accumulates close to these invaginations ( Paonessa et al, 2019 ), with evidence suggesting that liquid-liquid phase separation of tau at the nuclear envelope might be a possible initiating event in tauopathies ( Kang et al, 2021 ). In fact, while our study was under review, an independent group also reported that the loss of function of either ANKLE2 or BANF1 resulted in increased tau aggregation, an outcome that was proposed to be caused by damage to the nuclear envelope, allowing for the leakage of nuclear components into the cytoplasm, which eventually triggers tau aggregation ( Prissette et al, 2022 ). However, what is not clear is why cells with leaking nuclear components do not spontaneously develop tau aggregation, but rather require exogenous tau seeds to trigger tau aggregation ( Prissette et al, 2022 ), as we also reported in this study.…”

Section: Discussionmentioning

confidence: 90%

“…In fact, while our study was under review, an independent group also reported that the loss of function of either ANKLE2 or BANF1 resulted in increased tau aggregation, an outcome that was proposed to be caused by damage to the nuclear envelope, allowing for the leakage of nuclear components into the cytoplasm, which eventually triggers tau aggregation ( Prissette et al, 2022 ). However, what is not clear is why cells with leaking nuclear components do not spontaneously develop tau aggregation, but rather require exogenous tau seeds to trigger tau aggregation ( Prissette et al, 2022 ), as we also reported in this study. Apart from the role of BANF1 in nuclear envelope integrity, mutations in its gene can cause a human progeroid syndrome ( Puente et al, 2011 ), and it appears that BANF1 is also crucial for restoring the capacity to repair oxidative lesions ( Bolderson et al, 2019 ).…”

Section: Discussionmentioning

confidence: 90%

“…Our analysis revealed 23 genes (false discovery rate, FDR, < 5%; Table S1) that were positively enriched in FRET-positive cells with tau aggregation ( Fig 1F ). Two of our 23 top hits, CHMP6 and VPS13A (FDR < 5%; Table S1), had been previously reported as regulators of endosomal integrity during tau aggregation ( Chen et al, 2019 ), whereas BANF1 (FDR < 5%; Table S1) was recently identified in a CRISPR knockout screen with tau biosensor cells from an independent group ( Prissette et al, 2022 ). Furthermore, when the first 200 top gene hits, selected based on robust ranking aggregation from MAGeCK ( Li et al, 2014 ), were analyzed for pathway and protein complex enrichment using GO-BP (gene ontology-biological process) and GO-CC (gene ontology-cellular component) annotations, they were found to be primarily enriched in pathways of the late endosome, autophagosome, and tethering complexes coordinating endosome and lysosome fusion, suggesting an increase in tau aggregation due to a loss of function of genes with a role in autophagy and late endosomes ( Fig 1G ).…”

Section: Resultsmentioning

confidence: 99%

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CRISPRi screening reveals regulators of tau pathology shared between exosomal and vesicle-free tau

et al. 2022

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The aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer’s disease and other tauopathies. Tau pathology is believed to be driven by free tau aggregates and tau carried within exosome-like extracellular vesicles, both of which propagate trans-synaptically and induce tau pathology in recipient neurons by a corrupting process of seeding. Here, we performed a genome-wide CRISPRi screen in tau biosensor cells and identified cellular regulators shared by both mechanisms of tau seeding. We identified ANKLE2, BANF1, NUSAP1, EIF1AD, and VPS18 as the top validated regulators that restrict tau aggregation initiated by both exosomal and vesicle-free tau seeds. None of our validated hits affected the uptake of either form of tau seeds, supporting the notion that they operate through a cell-autonomous mechanism downstream of the seed uptake. Lastly, validation studies with human brain tissue also revealed that several of the identified protein hits are down-regulated in the brains of Alzheimer’s patients, suggesting that their decreased activity may be required for the emergence or progression of tau pathology in the human brain.

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“…In Drosophila, genetic manipulation of actin polymerization and LINC complex components mediates tau-induced neurodegeneration and nuclear architectures changes, demonstrating a causal link between the effects of tau on the actin cytoskeleton, the LINC complex, the lamin nucleoskeleton and neurodegeneration ( Frost et al, 2016 ). Recent studies in cultured cells and primary mouse tissue suggest that disruption of nuclear envelope integrity is a possible initiating event in tauopathies ( Prissette et al, 2022 ). While there is thus a clear breakdown of the nucleoskeleton and morphological changes in neuronal nuclei in the context of tauopathy, no study to date has investigated the mechanical properties of nuclei within cells harboring pathogenic forms of tau.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic tau decreases nuclear tension in cultured neurons

Sohn¹,

Ray

et al. 2023

Front. Aging

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Neurodegenerative tauopathies, including Alzheimer’s disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer’s disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.

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Disruption of nuclear envelope integrity as a possible initiating event in tauopathies

Cited by 27 publications

References 63 publications

Modeling Alzheimer’s disease in primary neurons reveals DNA damage response coupled with MAPK-DLK signaling in wild-type tau-induced neurodegeneration

Modeling Alzheimer’s disease in primary neurons reveals DNA damage response coupled with MAPK-DLK signaling in wild-type tau-induced neurodegeneration

CRISPRi screening reveals regulators of tau pathology shared between exosomal and vesicle-free tau

Pathogenic tau decreases nuclear tension in cultured neurons

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