CRISPR Screen Used to Uncover Tau-Clearing Protein

At the University of California, San Francisco, scientists have conducted a genome-wide CRISPR screen in iPSC-derived neurons to uncover a cellular cleanup system that protects neurons from the toxic tau protein linked to Alzheimer’s and other dementias. Their systematic genetic screen revealed that a protein called CUL5 acts as a waste collector, disposing of tau before it can form harmful clumps inside brain cells.

The research, published in Cell, shows how precision genetic tools can expose the molecular defenses that keep neurons alive. “CUL5 is uniquely suited to getting rid of tau,” said Martin Kampmann, senior author of the study. “Maybe a future therapy could enhance the body's natural mechanism for avoiding neurodegeneration.”.

To pinpoint genes that influence tau buildup, the team built a petri‑dish model of human neurons that were genetically engineered to produce tau clumps. They then used CRISPR technology to disable every one of the roughly 20,000 genes in the human genome, one by one, measuring how each loss affected the formation of tau tangles. This comprehensive screen gave a direct view of the cell’s internal defenses, revealing CUL5 as a key factor that tags tau for elimination before it can aggregate.

The researchers next asked whether the same process might operate in human patients. They examined data from the Seattle Alzheimer’s Disease Brain Atlas, which collects information from donated brain tissues. Even in brains damaged by Alzheimer’s, some neurons were notably more resilient; those cells contained abundant CUL5, suggesting that the protein protects against tau‑induced degeneration.

Beyond CUL5, the CRISPR test uncovered another set of genes tied to oxidative stress. Higher oxidative stress made tau more adhesive and more likely to form clusters.

“It's the first time we've been able to screen human neurons for genes that determine their resilience to tau,” Kampmann said. “We hope that CUL5 can be the first of many new targets for drug discovery against the dementias.”