Human Tau Mutations in Cerebral Organoids Induce a Progressive Dyshomeostasis of Cholesterol
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA859858 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20288900_1.fastq.gz | Fastqsanger.gz | |||
| SRR20288900_2.fastq.gz | Fastqsanger.gz | |||
| SRR20288901_1.fastq.gz | Fastqsanger.gz | |||
| SRR20288901_2.fastq.gz | Fastqsanger.gz | |||
| SRR20288902_1.fastq.gz | Fastqsanger.gz |
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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 with isogenic controls by single-cell RNA sequencing (scRNA-seq). 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.
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Project description:The microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer’s disease and numerous other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localization and a vast array of post-translational modifications, including phosphorylation, that progressively result in the protein’s aggregation and dysregulation of multiple Tau-dependent cellular processes. Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterize tauopathies, we asked targeting Tau would restore the proteomic dyshomeostasis observed in disease. To this end, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralizes proteopathic seeding activity in multiple cell-lines, and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We next evaluated both antibodies, alone and in combination, in the K3 mouse model of tauopathy, showing reduced Tau pathology and improved neuronal functions, without obtaining synergistic effects for the combination treatment. Quantitative proteomics revealed deregulation of metabolic and microtubule-associated proteins in K3 compared to wild-type brain, strengthening previously reported findings of functional defects in multiple tauopathy models. Importantly, both treatments, in particular RNJ1, reversed protein and phospho-protein dyshomeostasis for both increased and decreased proteins in the K3 brain, shifting levels towards those observed in wild-type mice. Gene set over-representation analysis further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced reversal of proteomic dyshomeostasis links target engagement and treatment efficacy.
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Project description:The microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer’s disease and numerous other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localization and a vast array of post-translational modifications, including phosphorylation, that progressively result in the protein’s aggregation and dysregulation of multiple Tau-dependent cellular processes. Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterize tauopathies, we asked targeting Tau would restore the proteomic dyshomeostasis observed in disease. To this end, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralizes proteopathic seeding activity in multiple cell-lines, and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We next evaluated both antibodies, alone and in combination, in the K3 mouse model of tauopathy, showing reduced Tau pathology and improved neuronal functions, without obtaining synergistic effects for the combination treatment. Quantitative proteomics revealed deregulation of metabolic and microtubule-associated proteins in K3 compared to wild-type brain, strengthening previously reported findings of functional defects in multiple tauopathy models. Importantly, both treatments, in particular RNJ1, reversed protein and phospho-protein dyshomeostasis for both increased and decreased proteins in the K3 brain, shifting levels towards those observed in wild-type mice. Gene set over-representation analysis further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced reversal of proteomic dyshomeostasis links target engagement and treatment efficacy.
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