Scientists find ‘master regulator’ that could reverse brain aging

The findings suggest that a single immune related protein may influence several processes involved in how the brain deteriorates over time.

Turning Off OTULIN Stops Toxic Tau

In a study published in the journal Genomic Psychiatry, the research team found that disabling OTULIN completely stopped tau production and removed existing tau from neurons. They achieved this by either using a specially designed small molecule or by knocking out the gene responsible for making OTULIN.

The experiments were carried out in two types of human cells. One group came from a patient who had died from 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.

New Possibilities for Treating Alzheimer's

The discovery could open new avenues for treating Alzheimer's disease and other neurodegenerative conditions, according to Karthikeyan Tangavelou, PhD, a senior scientist in the laboratory of Kiran Bhaskar, PhD, a professor in the Department of Molecular Genetics & Microbiology at the UNM School of Medicine.

"Pathological tau is the main player for both brain aging and neurodegenerative disease," Tangavelou said. "If you stop tau synthesis by targeting OTULIN in neurons, you can restore a heathy brain and prevent brain aging."

From Cellular Cleanup to Tau Control

The gene that encodes OTULIN (an acronym for "OTU deubiquitinase with linear linkage specificity") provides instructions for making a protein involved in inflammation control and autophagy. Autophagy is the process cells use to clear away damaged proteins and other waste.

Researchers were originally studying OTULIN for its role in cellular cleanup when they discovered its unexpected influence on tau production. Tangavelou described the finding as a "groundbreaking discovery that will be helpful to solve a complex puzzle in various neurological diseases and aging of the brain."

Why Tau Matters in Neurodegenerative Disease

Under normal conditions, tau helps stabilize microtubules that give neurons their structure. Problems arise when tau undergoes phosphorylation, a chemical modification that causes it to form tangled clumps inside neurons. These neurofibrillary tangles are a defining feature of Alzheimer's disease and more than 20 other neurodegenerative disorders, collectively known as tauopathies.

As treatments targeting amyloid beta plaques have shown limited clinical benefit, researchers have increasingly shifted their focus toward tau. Bhaskar's lab has already developed (and is planning to test in patients) a vaccine designed to prevent the buildup of toxic tau proteins.

Neurons Survive Without Tau

The study also revealed another unexpected result. When OTULIN was deactivated and tau disappeared, neurons showed no signs of damage or stress.

"Neurons can survive without tau," Tangavelou said. "They are looking healthy, even with the tau removed."

Exploring OTULIN Across Brain Cell Types

Tangavelou emphasized that neurons are only one of many cell types in the brain. Others include astrocytes, microglia, oligodendrocytes and endothelial cells.

"We discovered OTULIN's function in neurons," he said. "We don't know how OTULIN functions in other cell types in the brain. If there is no OTULIN in microglia, that may cause auto-inflammation. We are testing OTULIN in different brain cell types to narrow down OTULIN as a therapeutic target for various brain cell diseases."

A Possible Master Regulator of Brain Aging

Suppressing OTULIN did more than remove tau. The researchers found that it also disrupted messenger RNA (mRNA) signaling and changed the activity of many genes.

"We believe that OTULIN is the master regulator of brain aging, because this protein regulates RNA metabolism," Tangavelou said. "Knocking out the OTULIN gene alters many dozens of genes, mainly in the inflammatory pathway."

To carry out the research, the team used CRISPR (clustered regularly interspaced short palindromic repeats) gene editing, pluripotent stem cell induction, large scale RNA sequencing, and computational drug design to create the small molecule that blocks OTULIN production.

What This Means for Future Brain Aging Research

According to Tangavelou, both normal aging and neurodegenerative disease involve an imbalance between protein creation and protein breakdown in the brain.

"OTULIN could be a key regulator in creating an imbalance between protein synthesis and degradation and may cause brain aging," he said.

The researchers say these findings open the door to many new lines of investigation.

"We are developing a project to study the role of OTULIN in brain aging. This is a great opportunity to develop many projects for further research to reverse brain aging and have a healthy brain."