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MAPK-DLK signaling coupled with DNA damage promotes intrinsic neurotoxicity associated with non-mutated tau

ABSTRACT: MAPK-DLK signaling coupled with DNA damage promotes intrinsic neurotoxicity associated with non-mutated tau

PROVIDER: PRJNA1032144 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26525818_1.fastq.gz	Fastqsanger.gz
	SRR26525818_2.fastq.gz	Fastqsanger.gz
	SRR26525819_1.fastq.gz	Fastqsanger.gz
	SRR26525819_2.fastq.gz	Fastqsanger.gz
	SRR26525820_1.fastq.gz	Fastqsanger.gz

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MAPK-DLK signaling coupled with DNA damage promotes intrinsic neurotoxicity associated with non-mutated tau

Project description: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. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, 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. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the MAPK-DLK axis and DNA damage response in the neuronal degenerative process.

2023-11-15 | GSE246259 | GEO

Bassoon contributes to tau-seed neurotoxicity and propagation.

Project description:Tau aggregates are critical pathological features of Alzheimer’s disease (AD) and other tauopathies. Growing evidence suggests that soluble tau aggregates trigger neurodegenerative phenotypes. However, the nature of the tau species and interactors involved in its aggregation and spreading remains unclear. By using size exclusion chromatography, mass spectrometry, and bioinformatic analysis, we identified Bassoon protein (BSN) as a significant tau interactor in PS19 mice, as well as in human AD and PSP cases. We also found that overexpression of BSN triggers the aggregation of tau and increase the tau seeding activity in vitro, and also exacerbates the degenerative phenotype in a Fly model for tauopathy. Knockdown of BSN significantly reduced tau spreading in PS19 mouse brains and destabilized the tau aggregates, leading to a reduction in the tau pathology in this model. Furthermore, BSN downregulation was able to restore the neurodegenerative phenotype in PS19 mice, observed in electrophysiology and behavioral tests. Our results identify BSN as a key interactor of tau spread and aggregation in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.

2023-03-11 | PXD027451 | Pride

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominates.

Project description:Cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. In this study, we evaluate transcriptomic changes at time-points preceding frank neuronal loss using a C. elegans model of tau and TDP-43 co-expression. We find significant differential expression and exon usage in genes enriched in multiple pathways including lipid metabolism and lysosomal degradation. We note that tau related changes largely resemble tau/TDP-43 changes. We test loss-of-function mutations in a subset of tau and TDP-43 responsive genes, identifying new modifiers of neurotoxicity. Characterizing early cellular responses to tau and TDP-43 co-pathology is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP-43 in AD.

2024-03-15 | GSE249339 | GEO

0N4R Tau and 0N4R Tau P301L Neuronal Interactomes

Project description:Human non-mutated 0N4R Tau and P301L mutant 0N4R Tau tagged at the N-terminus with eGFP were expressed in mouse (CD1) primary cortical neurons using adeno associated viruses to monitor early changes in the synaptic interactome beforethe onset of neuronal loss. Affinity purification mass spectrometry (AP-MS) combined with tandem mass tagging was used to quantitatively compate the non-mutated and P301L interactomes.

2024-07-03 | PXD044959 | Pride

Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Project description:Tau (MAPT) is a microtubule-associated protein causing frequent neurodegenerative diseases or inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA protection and P53 regulation suggests its involvement in cancer. Indeed, Tau expression correlates with cancer-specific survival or response to microtubule therapeutics. These data may imply common molecular pathways involved in the pathogenesis of neurodegenerative disorders and cancer. To bring new evidence that Tau represents a key protein in cancer, we present an in silico pan-cancer analysis of MAPT transcriptomic profile in over 11000 clinical samples and over 1300 pre-clinical samples provided by the TCGA and the DEPMAP datasets respectively. We completed this analysis by exploring a possible interplay of MAPT with wild-type or mutated P53. Then, we calculated the impact of MAPT expression on clinical outcome and drug response. Overall, the results support a relevant role of the MAPT gene in several cancer types, although the contribution of Tau to cancer appears to very much depend on the cellular context.

2022-11-27 | E-MTAB-8166 | biostudies-arrayexpress

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Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity

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NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation.

Project description:The altered function and/or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDAR-mediated toxicity is postulated to play a pivotal role.

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Tau promotes neurodegeneration through global chromatin relaxation

Project description:We performed H3K9me2-based ChIP-seq to identify regions of the Drosophila genome that are H3K9me2-depleted due to transgenic neuronal expression of human mutant tau. Examination of H3K9me2 histone methylation in 10 day old control and tau transgenic Drosophila heads.

2013-12-31 | E-GEOD-53719 | biostudies-arrayexpress

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