Neocortical tau propagation is a mediator of clinical heterogeneity in Alzheimer’s disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1190994 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31520658_1.fastq.gz | Fastqsanger.gz | |||
| SRR31520658_2.fastq.gz | Fastqsanger.gz | |||
| SRR31520659_1.fastq.gz | Fastqsanger.gz | |||
| SRR31520659_2.fastq.gz | Fastqsanger.gz | |||
| SRR31520660_1.fastq.gz | Fastqsanger.gz |
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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:Tau aggregates lead to progressive neurodegeneration in Alzheimer’s disease (AD) (ref). Neuron death is one of the hallmarks of neurodegeneration (ref). However, the pathological influence of neuronal death is undetermined, and the connection between Tau aggregates and neuronal death remains elusive. Here we demonstrated the essential role of neuron death in Tau-related neurodegeneration. Tau-neurons died in necroptosis, dependent on ZBP1 sensitized by Z-RNAs (an unusual left-handed conformation). Those endogenous Z-RNAs were transcripts of reactivated transposable elements (TEs) originally silenced in heterochromatin.
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