Researchers have identified a pivotal mechanism through which the brain enzyme OTULIN regulates the expression of tau, a protein linked to the formation of toxic tangles in Alzheimer’s disease. The study, published in Genomic Psychiatry, reveals OTULIN’s unexpected role as a master regulator of gene expression and RNA metabolism. This discovery, led by Dr. Kiran Bhaskar from the University of New Mexico Health Sciences Center and Dr. Francesca-Fang Liao from the University of Tennessee Health Science Center, could pave the way for novel therapeutic strategies for millions affected by Alzheimer’s and related dementias.
The research team initially aimed to determine if stabilizing a specific type of ubiquitin chain would aid in clearing toxic tau from neurons. Instead, they found that knocking out the OTULIN gene entirely led to the complete absence of tau production. “This was a paradigm shift in our thinking,” stated Dr. Liao. “OTULIN deficiency causes tau mRNA to vanish, resulting in significant alterations in how the cell processes RNA and manages gene expression.”
Key Discoveries in Tau Regulation
The study employed neurons derived from a patient with late-onset sporadic Alzheimer’s disease, which exhibited elevated levels of both OTULIN protein and phosphorylated tau compared to healthy controls. This correlation indicated that OTULIN could be contributing to disease progression. The researchers uncovered several critical insights:
- When OTULIN was completely removed from neuroblastoma cells, comprehensive RNA sequencing indicated that over 13,000 genes were downregulated, while nearly 800 were upregulated. Additionally, RNA transcripts showed even more dramatic changes, with 43,000 downregulated and over 1,100 upregulated.
- Pharmacological inhibition of OTULIN’s enzymatic activity with a novel small molecule inhibitor, UC495, effectively reduced phosphorylated tau levels in Alzheimer’s neurons, suggesting potential therapeutic benefits.
- The absence of OTULIN was found to upregulate numerous genes associated with RNA degradation and stability regulation, including components of the CCR4-NOT complex and various RNA-binding proteins linked to neurodegenerative diseases.
- Bulk RNA sequencing revealed significant downregulation of OTULIN long noncoding RNA in Alzheimer’s neurons, alongside decreased expression of melanoma antigen gene (MAGE) family members, which are known to activate ubiquitin ligases involved in protein quality control.
Implications for Alzheimer’s Treatment
The findings hold substantial implications for the treatment of tauopathies, a group of over 20 neurodegenerative diseases marked by toxic tau accumulation. “OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully rather than eliminate it completely,” Dr. Bhaskar remarked. “Complete loss causes widespread changes in cellular RNA metabolism that could have unintended consequences.”
The research demonstrated that partial inhibition with UC495 reduced pathological tau forms without eliminating total tau or causing apparent toxicity to neurons. This indicates a therapeutic window exists where OTULIN activity can be adjusted to beneficial levels. The team also found that OTULIN deficiency prevents the onset of autoinflammation in neurons by downregulating components of inflammatory pathways, providing further insight into how cells manage protein quality control and inflammatory responses.
Beyond its implications for Alzheimer’s treatment, the study sheds light on fundamental mechanisms of RNA metabolism regulation in neurons. The researchers noted upregulation of transcriptional repressors such as YY1 and SP3 in OTULIN-deficient cells, along with alterations in RNA-binding ubiquitin ligases like RC3H2 and MEX3C, which are involved in mRNA stability. “We’re essentially looking at a previously unknown checkpoint in gene expression,” explained Dr. Liao. “OTULIN appears to influence which genes get expressed and how long their RNA messages survive in cells.”
The study employed advanced techniques, including CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived neurons from Alzheimer’s patients and healthy controls, comprehensive bulk RNA sequencing, and computational drug design to identify the OTULIN inhibitor UC495. The researchers validated their findings across multiple cell types, ensuring relevance to human disease.
Looking ahead, the research team is focused on understanding how OTULIN influences gene expression and RNA metabolism at a molecular level. They are currently investigating whether calibrated OTULIN inhibition can effectively reduce tau pathology in animal models of Alzheimer’s disease. “This discovery opens up an entirely new research direction,” said Dr. Bhaskar. “We need to determine whether targeting OTULIN therapeutically can safely reduce tau accumulation without disrupting essential cellular functions.”
Additionally, the team is exploring why OTULIN long noncoding RNA is reduced in Alzheimer’s neurons and whether restoring its levels could normalize OTULIN protein expression and tau pathology. This research could significantly advance the understanding and treatment of Alzheimer’s disease.
For more detailed information, refer to the study: “The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons,” published in Genomic Psychiatry (2025). DOI: 10.61373/gp025a.0116.
