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Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations [bulk RNA-Seq]

ABSTRACT: Frontotemporal dementia (FTD) due to MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations due to the mutation that precede neurodegeneration. Mutant organoids show early upregulation of MAPT expresssion and glutamatergic signaling pathways, as well as regulators including the RNA-binding protein ELAVL4. By 6 months, tau-V337M organoids show specific loss of glutamatergic neuronsof layers affected in patients. Mutant neurons are susceptible to glutamate toxicity, which was rescued pharmacologically by treatment with the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede cell death, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171343 | GEO | 2021/07/26

REPOSITORIES: GEO

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Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutations [scRNA-Seq]

Project description:Frontotemporal dementia (FTD) due to MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations due to the mutation that precede neurodegeneration. Mutant organoids show early upregulation of MAPT expresssion and glutamatergic signaling pathways, as well as regulators including the RNA-binding protein ELAVL4. By 6 months, tau-V337M organoids show specific loss of glutamatergic neuronsof layers affected in patients. Mutant neurons are susceptible to glutamate toxicity, which was rescued pharmacologically by treatment with the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede cell death, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

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PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [1]

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Human Tau Mutations in Cerebral Organoids Induce a Progressive Dyshomeostasis of Cholesterol

Project description:Mutations in the MAPT gene that encodes tau lead to frontotemporal dementia (FTD) with pathology evident in both cerebral neurons and glia. Human cerebral organoids (hCOs) from individuals harboring pathogenic tau mutations can reveal the earliest downstream effects on molecular pathways within a developmental context generating interacting neurons and glia. We found that in hCOs carrying the V337M and R406W tau mutations, the cholesterol biosynthesis pathway in astrocytes was the top upregulated gene set compared to isogenic controls by scRNAseq. The 15 upregulated genes included HMGCR, ACAT2, STARD4, LDLR, and SREBF2. This result was confirmed in a homozygous R406W mutant cell line, by immunostaining and sterol measurements. Cholesterol abundance in the brain is tightly regulated by efflux and cholesterol biosynthetic enzyme levels in astrocytes, and dysregulation can cause aberrant phosphorylation of tau. Our findings suggest that cholesterol dyshomeostasis is an early event in the etiology of neurodegeneration caused by tau mutations.

2022-07-21 | GSE208418 | GEO

ZFN engineered hiPSC with the FTDP-17 associated MAPT IVS10+16 mutation w/wo additional P301S mutation

Project description:The development of an effective therapy against tauopathies like Alzheimer’s disease (AD) and frontotemporal dementia (FTD) remains challenging, partly due to limited access to fresh brain tissue, the lack of translational in vitro disease models and the fact that underlying molecular pathways remain to be deciphered. Several genes play an important role in the pathogenesis of AD and FTD, one of them being the MAPT gene encoding the microtubule-associated protein tau. Over the past few years, it has been shown that induced pluripotent stem cells (iPSC) can be used to model various human disorders and can serve as translational in vitro tools. Therefore, we generated iPSC harboring the pathogenic FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) associated mutations IVS10+16 with and without P301S in MAPT using Zinc Finger Nuclease technology. Whole transcriptome analysis of MAPT IVS10+16 neurons reveals neuronal subtype differences, reduced neural progenitor proliferation potential and aberrant WNT signaling. Notably, all phenotypes were recapitulated using patient-derived neurons. Finally, an additional P301S mutation causes an increased calcium bursting frequency, reduced lysosomal acidity and tau oligomerization. Altogether, these tau mutant iPSC lines allow us to study IVS10+16 and P301S mutations in an isogenic background and to unravel a potential link between pathogenic 4R tau expression and FTDP-17.

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Comparison of FTDP-17 IVS10+16 patient derived hiPSC and ZFN engineered hiPSC

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Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

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Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

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Targeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-Derived Neuronal Cell Models

Project description:Tauopathies are a family of neurodegenerative diseases characterized by a shared pathology of aberrant forms of tau protein accumulation leading to neuronal death in focal areas of the brain. Positron emission tomography (PET) tracers that bind to tau aggregates are used to aid diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01- 175 was designed to engage both tau and Cereblon (CRBN), a substrate receptor for the Cullin-4 RING E3 ubiquitin ligase family member (CRL4CRBN), to trigger tau ubiquitination and proteasomal degradation. QC-01-175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, which recapitulate disease phenotypes of tau accumulation, insolubility and toxicity. Furthermore, QC-01-175 had minimal effect on tau levels in neurons from healthy controls, indicating specificity for degradation of disease-relevant forms of tau. QC-01-175 also rescued vulnerability to stress in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau species formed in ex vivo FTD patient-derived neurons are amenable to targeted protein degradation, representing an important advance towards the development of a tau targeted therapeutic.

2019-03-26 | PXD012515 | Pride

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