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

Samelson, Avi J.; Ariqat, Nabeela; McKetney, Justin; Rohanitazangi, Gita; Bravo, C; Bose, Rudra Shekhar; Travaglini, Kyle J.; Lam, Victor L.; Goodness, Darrin; Ta, Thomas; Dixon, Gary; Marzette, Emily; Jin, Julianne; Tian, Ruilin; Tse, Eric; Abskharon, Romany; Pan, Henry S.; Carroll, Emma C.; Lawrence, Rosalie; Gestwicki, Jason E.; Rexach, Jessica E.; Eisenberg, David; Kanaan, Nicholas M.; Southworth, Daniel R.; Gross, John D.; Gan, Li; Swaney, Danielle L.; Kampmann, Martin

doi:10.1016/j.cell.2025.12.038

articleCellJan 28, 2026HYBRID OA

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

AJAvi J. Samelson NANabeela Ariqat JMJustin McKetney GRGita Rohanitazangi CBC Bravo

University of California, Los Angeles · University of California, San Francisco · +11 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

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 changing tau aggregation in vitro. These results systematically reveal principles of tau proteostasis in human neurons and suggest potential therapeutic targets for tauopathies.

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Topics & keywords

Topics

Keywords

Proteostasis
Frontotemporal dementia
Ubiquitin
Ubiquitin ligase
Function (biology)
C9orf72
Neurodegeneration
CRISPR

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