New research conducted by UCLA Health and UC San Francisco has identified why some brain cells are more resistant to the accumulation of tau protein, a substance associated with Alzheimer’s disease and related dementias. The study was published in the journal Cell.
The research team used a CRISPR-based genetic screening method on lab-grown human neurons to analyze how tau proteins accumulate. Tau is known for forming toxic clumps that can destroy neurons, leading to neurodegenerative diseases such as frontotemporal dementia and Alzheimer’s disease. Until now, it was unclear why certain types of neurons are more affected than others.
The scientists systematically knocked down individual genes using CRISPR technology in stem cell-derived human neurons to observe their impact on tau buildup. Among over 1,000 genes analyzed, they found that a protein complex called CRL5SOCS4 plays a significant role by tagging tau for degradation through the cell’s recycling system.
Dr. Avi Samelson, assistant professor of Neurology at UCLA Health and first author of the study, said: “We wanted to understand why some neurons are vulnerable to tau accumulation while others are more resilient. By systematically screening nearly every gene in the human genome, we found both expected pathways and completely unexpected ones that control tau levels in neurons.”
Further analysis of brain tissue from Alzheimer’s patients showed that higher levels of CRL5SOCS4 components correlated with better neuron survival despite tau accumulation.
The researchers also discovered an unexpected link between mitochondrial dysfunction—when the cell’s energy producers fail—and increased production of a specific 25 kilodalton fragment of tau protein. This fragment resembles NTA-tau, a biomarker detected in blood and spinal fluid samples from Alzheimer’s patients.
“This tau fragment appears to be generated 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 machine, causing it to improperly process tau.”
Lab experiments showed that this abnormal fragment changes how tau proteins aggregate, potentially affecting disease progression.
The findings suggest possible new therapeutic strategies: boosting CRL5SOCS4 activity could help clear harmful forms of tau from neurons; maintaining proteasome function during cellular stress might prevent formation of toxic fragments.
“What makes this study particularly valuable is that we used human neurons carrying an actual disease-causing mutation,” Samelson said. “These cells naturally have differences in tau processing, giving us confidence that the mechanisms we identified are relevant to human disease.”
Researchers also noted previously unknown pathways involved in regulating tau—including UFMylation (a type of protein modification) and enzymes linked to building membrane anchors—were uncovered during their systematic genetic screen.
While these results provide several leads for drug development or therapies targeting neurodegenerative diseases like Alzheimer’s, further research will be necessary before clinical applications can be developed.
Funding for this work came from sources including the Rainwater Charitable Foundation/Tau Consortium and the National Institutes of Health.
