In a surprising discovery, University of New Mexico researchers have found that OTULIN – an enzyme that helps regulate the immune system – also drives the formation of tau, a protein implicated in many neurodegenerative diseases, as well as brain inflammation and aging.
In a study published in the journal Genomic Psychiatry , the researchers reported that when they deactivated OTULIN, either by administering a custom-designed small molecule or knocking out the gene that codes for it, it halted the production of tau and removed it from neurons. The study was conducted on two different types of cells, some derived from a patient who had died from late-onset sporadic Alzheimer's disease, and the rest from a line of human neuroblastoma cells that are frequently used in neuroscience research.
The discovery opens the door to potential treatments for Alzheimer's and other neurodegenerative diseases, said Karthikeyan Tangavelou, PhD, a senior scientist in the lab of Kiran Bhaskar, PhD, professor in the Department of Molecular Genetics & Microbiology in 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."
The gene coding for OTULIN (an acronym for "OTU deubiquitinase with linear linkage specificity") contains instructions for making a protein that regulates inflammation and autophagy, a mechanism that clears protein aggregates and other debris from within cells. The researchers were initially investigating the part played by OTULIN in removing cellular waste when they came upon its unexpected role in controlling tau production. Tangavelou calls it a "groundbreaking discovery that will be helpful to solve a complex puzzle in various neurological diseases and aging of the brain."
Tau normally stabilizes microtubules that help give structure to neurons, but when it is chemically altered in a process called phosphorylation it creates the neurofibrillary tangles within neurons that are characteristic of Alzheimer's and more than 20 other neurodegenerative diseases – collectively known as tauopathies.
Researchers are increasingly focusing on tau because immunotherapy drugs that reduce extracellular plaques of the better-known amyloid beta protein in the brains of dementia patients appear to have little clinical benefit. Bhaskar's lab has already developed (and is planning to test in patients) a vaccine that prevents the buildup of toxic tau proteins.
The new study by Bhaskar, Tangavelou and colleagues at UNM and the University of Tennessee made another unexpected finding. When they made tau disappear by de-activating the OTULIN gene, the neurons appear to be unaffected. "Neurons can survive without tau," Tangavelou said. "They are looking healthy, even with the tau removed."
He also notes that there are many other types of cells in the brain apart from neurons, including 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."
The study also found that when they suppressed OTULIN, it affected messenger RNA (mRNA) signaling and altered the expression of numerous 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."
The team used CRISPR (clustered regularly interspaced short palindromic repeats) gene editing technology, pluripotent stem cell induction, comprehensive bulk RNA sequencing and computational drug design to create the small molecule that was used to inhibit OTULIN formation in the study.
There is an imbalance between protein synthesis and degradation during normal brain aging and accelerated brain aging in diseased brains, Tangavelou said. "OTULIN could be a key regulator in creating an imbalance between protein synthesis and degradation and may cause brain aging," he said.
The new discoveries point the way to multiple new avenues of investigation, he said. "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."
