Scientists at UCLA Health and the University of California, San Francisco have discovered why certain brain cells are better able than others to withstand build-up of tau, a toxic protein closely associated with Alzheimer’s disease and related dementias. The discovery points to biological differences that may help explain why some neurons survive longer and could open the door to new therapeutic strategies.
Research published in journals cellrelied on advanced CRISPR-based genetic screening techniques in human neurons grown in the laboratory. The goal was to map the internal systems that control how tau accumulates within brain cells. When tau forms clumps, it damages and eventually kills neurons, causing conditions such as frontotemporal dementia and Alzheimer’s disease. Tau is the most common protein known to aggregate in neurodegenerative diseases, but scientists have long been puzzled as to why some neurons are more vulnerable than others.
CRISPR screening reveals tau purification system
The researchers systematically tested which genes influence tau accumulation using human neurons grown in the lab and a gene silencing tool called CRISPRi. Their large-scale screen highlighted a protein complex known as CRL5SOCS4. This complex labels tau with a molecular tag and directs it to the cell’s waste disposal system for degradation and removal.
The results suggest that promoting this natural clearing pathway could form the basis of new treatments for neurodegenerative diseases that affect millions of Americans but still lack effective treatments.
“We wanted to understand why some neurons are vulnerable to tau accumulation while others are more resilient,” said study lead author Avi Samelson, Ph.D., assistant professor of neurology at UCLA Health, who conducted the study while at UCSF. “By systematically screening nearly every gene in the human genome, we discovered both expected and completely unexpected pathways that control tau levels in neurons.”
In experiments using neurons derived from human stem cells, the researchers turned off individual genes to see how each gene affected the aggregation of toxic tau. Among the more than 1,000 genes flagged in the screen, CRL5SOCS4 stood out. It works by attaching a chemical marker to tau and signaling the cell’s recycling machinery to destroy the tau.
When the researchers examined brain tissue from Alzheimer’s patients, they found that neurons with higher levels of the CRL5SOCS4 component were more likely to survive despite tau accumulation.
Mitochondrial stress and harmful tau fragments
The study also revealed an unexpected link between mitochondrial problems and tau toxicity. Mitochondria function as the cell’s energy generators. When the researchers disrupted these energy-producing structures, the cells began producing a specific tau fragment of about 25 kilodaltons. This fragment closely matches a biomarker detected in the blood and spinal fluid of Alzheimer’s patients known as NTA-tau.
“This tau fragment appears to be produced when cells experience oxidative stress, which is common in aging and neurodegeneration,” Samelson said. “We found that this stress reduces the efficiency of the proteasome, the cell’s protein recycling machinery, and causes tau to be disposed of inappropriately.”
Laboratory experiments have shown that this altered tau fragment changes the way tau proteins cluster, which may influence disease progression.
A new path to Alzheimer’s disease treatment
This finding suggests several potential therapeutic directions. Increased CRL5SOCS4 activity may help neurons clear tau more effectively. At the same time, protecting the proteasome during periods of cellular stress may reduce the formation of harmful tau fragments.
“What makes this study particularly valuable is that it used human neurons that actually carried disease-causing mutations,” Professor Samelson said. “These cells naturally differ in tau processing, giving us confidence that the mechanisms we have identified are relevant to human disease.”
Beyond CRL5SOCS4, large-scale genetic screens have revealed additional biological pathways not previously associated with tau regulation. These include a protein modification process known as UFMylation and enzymes that help build membrane anchors within cells.
Although the results are promising, the researchers caution that more research is needed before these findings can be translated into treatments.
This research was funded by the Rainwater Charitable Foundation/Tau Consortium, the National Institutes of Health, and other funders.
