New research by UCLA Health and UC San Francisco has uncovered why certain brain cells are more resilient than others to the buildup of a toxic protein that is a hallmark of Alzheimer's disease and related dementias, potentially leading to new targets for therapies or treatments.
The study , published in the journal Cell, used a novel CRISPR-based genetic screening approach on lab-grown human brain cells to determine the cellular machinery that controls the accumulation of tau protein in the brain. These proteins can build up as toxic clumps in the brain, killing neurons and leading to neurodegenerative diseases such as frontotemporal dementia and Alzheimer's disease. Tau is the most common protein that aggregates in neurodegeneration diseases. However, researchers had not determined why some types of neurons are affected more than others.
UCLA and UCSF researchers used lab-grown neurons and the CRISPRi gene editing tool to systematically determine which genes and cell processes affect how tau proteins build up. The work identified a protein complex called CRL5SOCS4 that marks tau for degradation. The findings suggest that strengthening this natural defense mechanism could represent a new therapeutic strategy for neurodegenerative diseases, which affect millions of Americans but currently have no effective treatments.
"We wanted to understand why some neurons are vulnerable to tau accumulation while others are more resilient," said study first author Dr. Avi Samelson , assistant professor of Neurology at UCLA Health, who conducted the research while at UCSF. "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."
Using CRISPR gene-editing technology in neurons derived from human stem cells, the research team tested how knocking down individual genes affected the buildup of toxic tau clumps. Among more than 1,000 genes identified, the CRL5SOCS4 protein complex emerged as a key player that attaches molecular tags to tau, marking it for destruction by the cell's recycling machinery.
Importantly, analysis of brain tissue from Alzheimer's patients revealed that higher expression of CRL5SOCS4 components made neurons more likely to survive despite the accumulation of tau protein.
The study also revealed an unexpected connection between mitochondrial dysfunction and tau toxicity. When the researchers disrupted the cellular powerhouses that generate energy, they triggered the production of a specific tau fragment approximately 25 kilodaltons in size. This fragment closely resembles a biomarker found in the blood and spinal fluid of Alzheimer's patients, known as NTA-tau.
"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."
The researchers demonstrated that this abnormal tau fragment changes how tau proteins clump together in test tube experiments, potentially influencing disease progression.
The findings provide several promising leads for therapeutic development. Enhancing CRL5SOCS4 activity could help neurons clear tau more effectively, while strategies to maintain proteasome function during stress might prevent the formation of toxic tau 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."
The research also highlights the power of systematic genetic screening to reveal disease mechanisms. The team identified several unexpected pathways including a protein modification system called UFMylation and enzymes involved in building cellular membrane anchors, that had not previously been linked to tau regulation.
While the findings are promising, researchers emphasized that translating these discoveries into treatments will require additional research.
The study was funded by the Rainwater Charitable Foundation/Tau Consortium, the National Institutes of Health and other sources.
