Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA749056 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15218024.fastq.gz | Fastqsanger.gz | |||
| SRR15218025.fastq.gz | Fastqsanger.gz | |||
| SRR15218026.fastq.gz | Fastqsanger.gz | |||
| SRR15218027.fastq.gz | Fastqsanger.gz | |||
| SRR15218028.fastq.gz | Fastqsanger.gz |
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Project description:Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.
2024-01-18 | GSE180672 | GEO
Project description:Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Here, we engineered new human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer’s Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
2024-04-08 | GSE255904 | GEO
Project description:Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Here, we engineered new human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer’s Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
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Project description:Pathogenic a-synuclein and tau are critical drivers of neurodegeneration and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type specific a-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain- wide single-cell RNA sequencing of >200 live neuron types in fruit flies to ask which cellular environments react most to a-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of a-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic a-synuclein or tau. By uncovering synapse and Ca2+ homeostasis related genes as tau toxicity modifiers our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.
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Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
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Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
2022-03-10 | GSE198013 | GEO
Project description:Pathogenic tau accumulation fuels neurodegeneration in Alzheimer’s disease (AD). The role of microglia in tau-driven neurodegeneration is intricate, with DAP12 (DNAX-activation protein 12) triggering microglial immune responses. Mice lacking DAP12 become resistant to tau-induced brain toxicity in tauopathy mice, yet the precise mechanism remains elusive. Our current study uncovers a novel resilience mechanism against tau toxicity conferred by Dap12 deletion. While inactivation of Dap12 elevates tau inclusions, potentially disrupting microglial tau processing, it curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli) are abolished by removal of Dap12. Additionally, AD brains exhibit mouse iOli-like cells spatially correlated with tau pathology. In summary, our study reveals that DAP12 signaling triggers toxic interactions between microglia and oligodendrocytes in tauopathy, mediating tau-induced damage to oligodendrocytes and synaptic loss. Targeting DAP12 signaling presents a promising therapeutic approach for enhancing resilience against tau toxicity in AD.
2025-10-23 | GSE246090 | GEO
Project description:Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. The link between mutations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a microglia-expressed gene, and the increased risk for developing late-onset AD suggests a detrimental role for microglia in disease pathophyioslogy. Hemizygous TREM2 mutations are posited to increase risk for AD through loss-of-function haploinsufficiency. The effects of TREM2 haploinsufficiency on tau pathology and tau-associated deficits have not yet been characterized. Using in vivo imaging, we showed that TREM2 haploinsufficiency, but not complete loss of TREM2, resulted in a striking agedependent impairment in microglia’s response to injury without affecting baseline motility. This TREM2-dependent effect on microglial motility is consistent with transcriptomic alterations in cell motility uncovered with unbiased RNAsequencing analysis. Moreover, TREM2 haploinsufficiency, but not complete loss of TREM2, exacerbated phosphorylated tau pathology in transgenic mice expressing mutant human tau. In addition, TREM2 haploinsufficiency increased tau inclusions and tau-mediated inflammation without further exacerbating neuronal loss. Our findings demonstrate for the first time that TREM2 haploinsufficiency induces deficits in a tauopathy mouse model, supporting the notion that the hemizygous missense variant results in loss-of-function.
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Project description:Neuronal identity defines a-synuclein and tau toxicity
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Project description:One of the defining pathological features of Alzheimer’s Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.
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