Scientists Discover “Master Regulator” that Could Reverse Brain Aging

Scientists at the University of New Mexico have discovered an unexpected link between the immune system and brain health. Their research shows that OTULIN, an enzyme known for regulating immune activity, also plays an important role in the production of tau, a protein closely associated with Alzheimer’s disease, other neurodegenerative diseases, brain inflammation, and aging processes. The findings suggest that a single immune-related protein can influence multiple processes that contribute to brain aging.

New Nossibilities for Treating Alzheimer’s Disease

In a study published in the journal Genomic Psychiatry, the research team found that deactivating OTULIN completely stopped tau production and removed existing tau from neurons. They achieved this either by using a specially developed small molecule or by switching off the gene responsible for the production of OTULIN. The experiments were conducted on two types of human cells. One group came from a patient who had died of late-onset sporadic Alzheimer’s disease. The other came from a commonly used line of human neuroblastoma cells that serve as a standard model in neuroscience research.

The discovery could open up new avenues for treating Alzheimer’s and other neurodegenerative diseases, according to Karthikeyan Tangavelou, PhD, a senior scientist in the laboratory of Kiran Bhaskar, PhD, professor in the Department of Molecular Genetics and Microbiology at the UNM School of Medicine. “Pathological tau is the main factor in both brain aging and neurodegenerative diseases,” Tangavelou said. “By stopping tau synthesis through targeted manipulation of OTULIN in neurons, you can restore a healthy brain and prevent brain aging.”

Why Tau Plays a Role in Neurodegenerative Diseases

The gene that encodes OTULIN (an abbreviation for “OTU deubiquitinase with linear linkage specificity”) provides the instructions for making a protein involved in inflammation control and autophagy. Autophagy is the process by which cells remove damaged proteins and other waste materials. The researchers were originally investigating OTULIN for its role in cell cleanup when they discovered its unexpected influence on tau production. Tangavelou described the finding as “a groundbreaking discovery that will help solve a complex puzzle in various neurological diseases and brain aging.”

Under normal conditions, tau helps stabilize the microtubules that give neurons their structure. Problems arise when tau undergoes phosphorylation, a chemical change that causes it to clump together into tangled masses within neurons. These neurofibrillary tangles are a hallmark of Alzheimer’s disease and more than 20 other neurodegenerative disorders collectively known as tauopathies. Since treatments targeting amyloid-beta plaques have shown limited clinical benefit, researchers have increasingly shifted their focus to tau. Bhaskar’s lab has already developed a vaccine (and plans to test it in patients) designed to prevent the accumulation of toxic tau proteins.

Neurons Survive Without Tau

The study also revealed another unexpected finding. When OTULIN was deactivated and tau disappeared, the neurons showed no signs of damage or stress. “Neurons can survive without tau,” Tangavelou said. “They look healthy even when tau is removed.”

Tangavelou emphasized that neurons are just one of many cell types in the brain. Others include astrocytes, microglia, oligodendrocytes, and endothelial cells. “We discovered the function of OTULIN in neurons,” he said. “We don’t know how OTULIN works in other cell types in the brain. If there is no OTULIN in microglia, it can lead to autoinflammation. We are testing OTULIN in different brain cell types to narrow down OTULIN as a therapeutic target for various brain cell diseases.”

What this Means for Future Research on Brain Aging

Suppressing OTULIN did more than just remove tau. The researchers found that it also disrupted messenger RNA (mRNA) signaling and altered the activity of many genes. “We believe that OTULIN is the main regulator of brain aging because this protein regulates RNA metabolism,” Tangavelou said. “Turning off the OTULIN gene alters dozens of genes, mainly in the inflammatory pathway.” To conduct the research, the team used CRISPR (clustered regularly interspaced short palindromic repeats) gene editing, pluripotent stem cell induction, large-scale RNA sequencing, and computer-aided drug design to develop the small molecule that blocks OTULIN production.

According to Tangavelou, both normal aging and neurodegenerative diseases are associated with an imbalance between protein synthesis and protein degradation in the brain. “OTULIN could be an important regulator of the imbalance between protein synthesis and degradation, potentially causing brain aging,” he said. The researchers say these findings open the door to many new research approaches. “We are developing a project to investigate the role of OTULIN in brain aging. This is a great opportunity to develop many projects for further research to reverse brain aging and maintain a healthy brain.”