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CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

ABSTRACT: Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimers disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, subsequent dysfunction, and death. However, molecular mechanisms underlying cell type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi screen in iPSC-derived neurons. The screen uncovered both known and unexpected pathways, including UFMylation and GPI anchor biosynthesis, that control tau oligomer levels. We discovered that the E3 ubiquitin ligase CUL5SOCS4 controls tau levels in human neurons, ubiquitinates tau, and is correlated with resilience to tauopathies in human disease. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, generating disease-relevant tau proteolytic fragments and changes tau aggregation in vitro. These results systematically reveal principles of tau proteostasis in human neurons and suggest potential therapeutic targets for tauopathies.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Danielle Swaney Martin Kampmann

PROVIDER: MSV000100129 | MassIVE | Fri Dec 05 15:07:00 GMT 2025

SECONDARY ACCESSION(S): PXD071655

REPOSITORIES: MassIVE

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