Scientists have uncovered a previously unknown function of the enzyme OTULIN in regulating the production of tau, the protein that aggregates in neurodegenerative diseases such as Alzheimer’s. Rather than just managing protein degradation, OTULIN appears to serve as a “master regulator” of tau gene expression, a discovery that could radically shift therapeutic strategies.
In a study published in Genomic Psychiatry, the research team led by Dr. Kiran Bhaskar (University of New Mexico) and Dr. Francesca-Fang Liao (University of Tennessee) explored how neurons clear toxic tau aggregates. Surprisingly, when they completely removed the OTULIN gene from neurons, tau protein didn’t just degrade faster — it almost vanished entirely. This was not due to enhanced cleanup: rather, tau mRNA itself disappeared, suggesting that OTULIN is crucial for the production of tau at the transcriptional level.
The team’s experiments revealed sweeping changes in gene expression: in OTULIN-deficient cells, over 13,000 genes were downregulated and hundreds more were upregulated. Similarly, in neurons derived from Alzheimer’s patients, thousands of genes and RNA transcripts showed altered expression when compared to healthy control neurons.
To explore translational possibilities, the researchers tested a small-molecule inhibitor named UC495, which targets OTULIN’s enzymatic activity. Unlike full gene knockout, partial inhibition with UC495 reduced phosphorylated (pathologic) tau levels in human Alzheimer’s neurons — but didn’t eliminate all tau, and seemed less toxic to cells. This suggests a “therapeutic window” where OTULIN’s activity can be modulated safely.
Beyond tau, OTULIN deficiency also triggered upregulation of genes involved in RNA stability and degradation. Proteins of the CCR4-NOT complex, various RNA-binding proteins linked to neurodegeneration, and transcriptional repressors like YY1 and SP3 were all affected — highlighting OTULIN’s broader role in RNA metabolism and gene regulation.
Interestingly, in Alzheimer’s neurons, the researchers found reduced levels of OTULIN long noncoding RNA (lncRNA), as well as lower expression of MAGE family genes that normally regulate ubiquitin ligases. These changes may influence how OTULIN itself is expressed, opening up potential new intervention points.
The implications are profound :
• Novel Drug Target: Instead of just clearing tau through traditional degradation pathways, new therapies might aim to modulate OTULIN’s activity to reduce tau production.
• Balancing Act: Total suppression of OTULIN can lead to widespread transcriptomic chaos, so partial inhibition might be the key.
• Broader Relevance: Since OTULIN is linked to RNA metabolism and key disease-associated RNA-binding proteins (like TDP-43, FMR1, ATXN2), these findings might extend to other neurodegenerative disorders beyond Alzheimer’s.
The researchers now plan to test OTULIN modulation in animal models, and to further unravel how it influences RNA stability at the molecular level. They’re also investigating whether restoring OTULIN lncRNA in Alzheimer’s neurons can re-balance its expression and reduce tau pathology.
This groundbreaking discovery transforms how we think about Alzheimer’s disease: not just as a problem of clearing harmful protein, but as one of controlling its production at the genetic level.
