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

Authors

Avi J. Samelson, University of California, San Francisco
Nabeela Ariqat, University of California, San Francisco
Justin McKetney, California Institute for Quantitative Biosciences
Gita Rohanitazangi, University of California, San Francisco
Celeste Parra Bravo, University of California, San Francisco
Rudra S. Bose, University of California, San Francisco
Kyle J. Travaglini, Allen Institute for Brain Science
Victor L. Lam, University of California, San Francisco
Darrin Goodness, University of California, San Francisco
Thomas Ta, University of California, San Francisco
Gary Dixon, University of California, San Francisco
Emily Marzette, University of California, San Francisco
Julianne Jin, University of California, San Francisco
Ruilin Tian, University of California, San Francisco
Eric Tse, University of California, San Francisco
Romany Abskharon, UCLA-DOE Institute for Genomics and Proteomics
Henry S. Pan, University of California, San Francisco
Emma C. Carroll, San Jose State UniversityFollow
Rosalie E. Lawrence, David Geffen School of Medicine at UCLA
For full author list, see comments below

Publication Date

1-28-2026

Document Type

Article

Publication Title

Cell

DOI

10.1016/j.cell.2025.12.038

Abstract

Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer’s disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, 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 induced pluripotent stem cell (iPSC)-derived neurons. The screen uncovered both known and unexpected pathways, including UFMylation and GPI anchor biosynthesis, which control tau oligomer levels. We discovered that the E3 ubiquitin ligase CRL5^SOCS4 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.

Funding Number

P30CA082103

Funding Sponsor

Alzheimer's Association

Keywords

CRISPR screen, CUL5, neurodegeneration, protein aggregation, proteostasis, SOCS4, tau

Comments

Full author list:

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

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Department

Chemistry

Recommended Citation

Samelson, A. J., Ariqat, N., McKetney, J., Rohanitazangi, G., Bravo, C. P., Bose, R. S., Travaglini, K. J., Lam, V. L., Goodness, D., Ta, T., Dixon, G., Marzette, E., Jin, J., Tian, R., Tse, E., Abskharon, R., Pan, H. S., Carroll, E. C., Lawrence, R. E., . . . Kampmann, M. (2026). CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. Cell, 189(5), 1517-1534.e19. https://doi.org/10.1016/j.cell.2025.12.038