Researchers at the University of New Mexico have identified that the enzyme OTULIN, known for its role in immune system regulation, also contributes to the formation of tau protein, brain inflammation, and aging. Pathological tau is a significant factor in both brain aging and neurodegenerative diseases.
Key Findings
When OTULIN was deactivated, either through a custom-designed small molecule or by knocking out its gene, the production of tau ceased, and existing tau was removed from neurons. This finding originated from a study published in "Genomic Psychiatry," conducted on human neuroblastoma cells and cells derived from an Alzheimer's patient.
This discovery may pave the way for new therapeutic approaches for Alzheimer's and other neurodegenerative conditions. Dr. Karthikeyan Tangavelou, a senior scientist on the team, indicated that targeting OTULIN in neurons to halt tau synthesis could restore brain health and prevent aging.
Initially, researchers were investigating OTULIN's role in autophagy—the cellular process of clearing waste—when its unexpected involvement in regulating tau production was observed. Tau protein typically stabilizes microtubules within neurons; however, when chemically altered through phosphorylation, it forms neurofibrillary tangles characteristic of Alzheimer's and over 20 other tauopathies.
Neurons were observed to remain healthy and unaffected despite the removal of tau following OTULIN gene deactivation. The study also revealed that suppressing OTULIN impacted messenger RNA (mRNA) signaling and altered the expression of numerous genes, predominantly those in the inflammatory pathway. Researchers suggest OTULIN acts as a master regulator of brain aging, influencing RNA metabolism and multiple genes.
Research Methods
The team utilized advanced techniques including CRISPR gene editing, pluripotent stem cell induction, bulk RNA sequencing, and computational drug design to develop the small molecule inhibitor.
Future Research
Further investigation into OTULIN's functions in other brain cell types, such as astrocytes and microglia, is planned. Researchers believe these findings open multiple avenues for understanding and potentially reversing brain aging.