Scientists have made a significant breakthrough in understanding how a brain enzyme known as OTULIN regulates the expression of tau, a protein linked to the formation of toxic tangles in Alzheimer’s disease. This pivotal discovery, published in the journal Genomic Psychiatry, reveals that OTULIN not only participates in protein degradation pathways but also serves as a critical regulator of gene expression and RNA metabolism.
The research team, 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, stumbled upon this unexpected role while exploring how neurons eliminate abnormal tau aggregates. Their findings could pave the way for new therapeutic strategies aimed at treating Alzheimer’s and related dementias that affect millions globally.
Unexpected Findings Shift Understanding of Tau Production
Initially, the researchers aimed to determine if stabilizing a specific type of ubiquitin chain would help neurons clear toxic tau. Instead, they discovered that knocking out the OTULIN gene led to a complete absence of tau—not due to enhanced degradation, but because the protein was not produced at all. “This was a paradigm shift in our thinking,” remarked Dr. Liao. The study found that OTULIN deficiency resulted in the disappearance of tau mRNA, significantly altering how cells process RNA and regulate gene expression.
The team utilized neurons derived from a patient with late-onset sporadic Alzheimer’s disease. These neurons exhibited elevated levels of both OTULIN protein and phosphorylated tau compared to healthy controls, indicating a potential role for OTULIN in disease progression. Comprehensive RNA sequencing revealed that when OTULIN was removed from neuroblastoma cells, more than 13,000 genes were downregulated, while approximately 774 genes were upregulated. The number of affected RNA transcripts was even higher, with over 43,000 downregulated and 1,113 upregulated.
Therapeutic Potential of OTULIN Inhibition
Further analysis indicated that pharmacological inhibition of OTULIN’s enzymatic activity using a novel small molecule inhibitor, UC495, led to a reduction in phosphorylated tau levels in Alzheimer’s neurons. This suggests that targeted therapeutic strategies could benefit patients without fully eliminating OTULIN’s gene activity. “We need to modulate its activity carefully rather than eliminate it completely,” Dr. Bhaskar emphasized, noting that the complete loss of OTULIN caused widespread changes in cellular RNA metabolism.
The research also highlighted that OTULIN deficiency reduces autoinflammation in neurons by downregulating components of inflammatory pathways. This finding adds another layer of understanding to how cells manage protein quality control alongside inflammatory responses.
The implications of this research extend beyond Alzheimer’s disease. It uncovers fundamental mechanisms of RNA metabolism regulation in neurons. The researchers noted an increase in transcriptional repressors such as YY1 and SP3 in OTULIN-deficient cells, along with alterations in RNA-binding ubiquitin ligases that influence mRNA stability. “We’re essentially looking at a previously unknown checkpoint in gene expression,” Dr. Liao explained, indicating that OTULIN may significantly influence gene expression and the longevity of RNA messages within cells.
The study utilized advanced techniques, including CRISPR-Cas9 gene editing and comprehensive bulk RNA sequencing, ensuring the findings are relevant to human diseases. The team plans to further explore how OTULIN affects gene expression and RNA metabolism at the molecular level, as well as whether fine-tuned OTULIN inhibition can mitigate tau pathology in animal models of Alzheimer’s disease.
“This discovery opens up an entirely new research direction,” concluded Dr. Bhaskar, highlighting the potential of OTULIN as a therapeutic target. The ongoing investigation aims to clarify the relationship between OTULIN long noncoding RNA and its reduced levels in Alzheimer’s neurons, which could have implications for restoring normal OTULIN protein expression and mitigating tau pathology.
For more information, refer to the study titled “The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons,” published in Genomic Psychiatry in 2025.
