CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis
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<sup>SOCS4</sup> 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.
Authors
- Eric Tse (ORCID: https://orcid.org/0000-0002-2082-9006)
- Rosalie Lawrence
- Ruilin Tian (ORCID: https://orcid.org/0000-0001-7680-6682)
- Justin McKetney (ORCID: https://orcid.org/0000-0002-2405-8288)
- C Bravo (ORCID: https://orcid.org/0000-0001-9781-8922)
- Gary Dixon (ORCID: https://orcid.org/0000-0002-6616-4740)
- Avi J. Samelson
- Daniel R. Southworth (ORCID: https://orcid.org/0000-0001-7108-9389)
- Rudra Shekhar Bose
- Victor L. Lam (ORCID: https://orcid.org/0000-0001-5384-6542)
- David Eisenberg (ORCID: https://orcid.org/0000-0003-2432-5419)
- Danielle L. Swaney (ORCID: https://orcid.org/0000-0001-6119-6084)
- Gita Rohanitazangi
- Darrin Goodness
- Emily Marzette
- Thomas Ta
- Li Gan
- Julianne Jin (ORCID: https://orcid.org/0009-0008-9877-9716)
- Martin Kampmann
- Jason E. Gestwicki
- Henry S. Pan
- Emma C. Carroll
- Nicholas M. Kanaan
- Nabeela Ariqat
- Jessica E. Rexach
Institutions
- QB3 (US)
- Allen Institute for Brain Science (US)
- Gladstone Institutes (US)
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- Cornell University (US)
- MIND Research Institute (US)
- Institute for Neurodegenerative Disorders (US)
- Allen Institute (US)
- Weill Cornell Medicine (US)
- San Jose State University (US)
- Michigan State University (US)
Publication Details
- Journal
- Cell
- Published
- 2026-01-28
- DOI
- https://doi.org/10.1016/j.cell.2025.12.038
- Citations
- 5
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 164.20
Funders
- Howard Hughes Medical Institute
- Alzheimer's Association
- BrightFocus Foundation
- Innovative Genomics Institute
- National Institute for Health and Care Research
- National Institutes of Health
- University of California, San Francisco