Scientists Discover Enzyme That Controls Tau Production in Alzheimer’s Disease
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Scientists have uncovered a surprising mechanism by which a brain enzyme called OTULIN controls the expression of tau, the protein that forms toxic tangles in Alzheimer’s disease. The findings, published in genomic Psychiatry, reveal that OTULIN functions not only as expected in protein degradation pathways but also plays a previously unkown role as a master regulator of gene expression and RNA metabolism.
The research team, led by Dr. Kiran Bhaskar at the University of New Mexico Health Sciences Center and Dr. Francesca-Fang Liao at the University of Tennessee Health Science Center, made the discovery while investigating how neurons clear abnormal tau aggregates. Their unexpected findings could open new therapeutic avenues for Alzheimer’s disease and related dementias affecting millions worldwide.
“We set out too test whether stabilizing a specific type of ubiquitin chain would help clear toxic tau from neurons,” explained Dr. bhaskar. “Instead, we discovered something completely unexpected-that OTULIN acts as a master switch controlling whether tau is even produced in the first place.”
The revolutionary discovery
The research team initially hypothesized that inhibiting OTULIN’s enzyme activity would enhance tau clearance through cellular garbage disposal systems. Though, when they completely knocked out the OTULIN gene in neurons, tau disappeared entirely-not as it was being degraded faster, but because it wasn’t being made at all.
“This was a paradigm shift in our thinking,” said Dr. Liao. “We found that OTULIN deficiency causes tau mRNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression.”
The study used neurons derived from a patient with late-onset sporadic Alzheimer’s disease, which showed elevated levels of both OTULIN protein and phosphorylated tau compared to healthy control neurons. This correlation suggested OTULIN might be contributing to disease progression.
New Target Identified for Alzheimer’s Disease Treatment: OTULIN
Researchers have identified a novel molecular target, OTULIN, that plays a critical role in regulating gene expression and RNA metabolism, offering a potential new avenue for treating Alzheimer’s disease. The study, conducted by teams at the University of California, San diego, and the Salk Institute for Biological Studies, reveals that OTULIN influences tau pathology – a hallmark of Alzheimer’s – by controlling the stability of RNA molecules.
The findings, published in Nature neuroscience, demonstrate that OTULIN interacts with key RNA-binding proteins and regulates the activity of ligases RC3H2 and MEX3C that control mRNA stability. “We’re essentially looking at a previously unknown checkpoint in gene expression,” explained Dr. Liao. “OTULIN appears to influence which genes get expressed and how long their RNA messages survive in cells.”
The study also revealed connections between OTULIN and multiple neurodegenerative disease-associated RNA-binding proteins, including TDP-43, FMR1, ATXN2, and MSI1, suggesting broader implications for understanding various brain disorders.
Research methodology
The team used cutting-edge techniques including CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived neurons from Alzheimer’s patients and healthy controls, comprehensive bulk RNA sequencing, and computational drug design to identify the OTULIN inhibitor UC495.
They validated their findings across multiple cell types, including patient-derived neurons and human neuroblastoma cells, ensuring reproducibility and relevance to human disease.
Next steps
The researchers are now working to understand precisely how OTULIN influences gene expression and RNA metabolism at the molecular level. They’re also testing whether carefully calibrated OTULIN inhibition can reduce tau pathology in animal models of Alzheimer’s disease.
“This discovery opens up an entirely new research direction,” said Dr. Bhaskar. “We need to determine whether targeting OTULIN therapeutically can safely reduce tau accumulation without disrupting essential cellular functions.”
The team is also investigating why OTULIN long noncoding RNA is reduced in Alzheimer’s neurons and whether restoring its levels could normalize OTULIN protein expression and tau pathology.
Citation: Novel discovery reveals how brain protein OTULIN controls tau expression and could transform Alzheimer’s treatment (2025, November 25) retrieved 25 November 2025 from https://medicalxpress.com/news/2025-11-discovery-reveals-brain-protein-otulin.html
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