Scientists have made a significant breakthrough in understanding the role of a brain enzyme known as OTULIN in the expression of tau protein, a key factor in the development of Alzheimer’s disease. Their findings, published in the journal Genomic Psychiatry, suggest that OTULIN not only participates in protein degradation pathways but also serves as a master regulator of gene expression and RNA metabolism. This discovery could pave the way for novel treatment strategies for Alzheimer’s and related dementias that affect millions globally.
The research team, led by Dr. Kiran Bhaskar at the University of New Mexico Health Sciences Center and Dr. Francesca-Fang Liao at the University of Tennessee Health Science Center, made this unexpected finding while investigating how neurons manage abnormal tau aggregates.
Dr. Bhaskar explained the motivation behind their research: “We set out to test whether stabilizing a specific type of ubiquitin chain would help clear toxic tau from neurons. Instead, we discovered something completely unexpected—that OTULIN acts as a master switch controlling whether tau is even produced in the first place.”
Unexpected Findings Alter Research Direction
Initially, the team believed that inhibiting OTULIN’s enzyme activity would enhance tau clearance through the cell’s waste disposal systems. However, when they completely knocked out the OTULIN gene in neurons, they observed that tau levels dropped significantly—not due to increased degradation, but because tau was not being produced at all. “This was a paradigm shift in our thinking,” noted Dr. Liao.
The research employed neurons derived from a patient with late-onset sporadic Alzheimer’s disease, revealing elevated levels of both OTULIN protein and phosphorylated tau compared to healthy neurons. This correlation suggests that OTULIN may contribute to the progression of the disease. The study yielded several critical insights, including:
1. Complete removal of OTULIN from neuroblastoma cells caused dramatic changes in gene expression, with 13,341 genes downregulated and 774 genes upregulated. RNA transcripts showed even more dramatic effects, with 43,003 downregulated and 1,113 upregulated.
2. Pharmacological inhibition of OTULIN’s enzymatic activity using a novel small molecule inhibitor, referred to as UC495, led to reduced levels of phosphorylated tau in Alzheimer’s neurons.
3. Absence of OTULIN upregulated multiple genes linked to RNA degradation and stability regulation, including elements of the CCR4-NOT complex and various RNA-binding proteins associated with neurodegenerative diseases.
4. Bulk RNA sequencing indicated significant downregulation of OTULIN long noncoding RNA in Alzheimer’s neurons, alongside decreased expression of melanoma antigen gene (MAGE) family members, which are involved in protein quality control.
Implications for Alzheimer’s Treatment
These findings have substantial implications for the treatment of tauopathies, a category of more than twenty neurodegenerative diseases characterized by toxic tau accumulation. According to Dr. Bhaskar, “OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully rather than eliminate it completely.”
The research indicates that partial inhibition with UC495 effectively reduced pathological tau forms without eliminating total tau or causing apparent toxicity to neurons. This suggests a therapeutic window exists, allowing for OTULIN activity to be fine-tuned to beneficial levels. Additionally, the team discovered that OTULIN deficiency helps prevent autoinflammation in neurons by downregulating components of inflammatory pathways, providing further insight into how cells maintain a balance between protein quality control and inflammatory responses.
Beyond its implications for Alzheimer’s, the study enhances the understanding of RNA metabolism regulation in neurons. The researchers noted an upregulation of transcriptional repressors such as YY1 and SP3 in OTULIN-deficient cells, along with alterations in RNA-binding ubiquitin ligases RC3H2 and MEX3C, which influence mRNA stability. “We’re essentially looking at a previously unknown checkpoint in gene expression,” explained Dr. Liao.
The research utilized advanced techniques, including CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived neurons from both Alzheimer’s patients and healthy controls, extensive bulk RNA sequencing, and computational drug design to identify the OTULIN inhibitor UC495.
The team validated their findings across multiple cell types, ensuring the relevance and reproducibility of their results for human disease.
Looking ahead, the researchers are focused on understanding precisely how OTULIN influences gene expression and RNA metabolism at the molecular level. They are also exploring whether carefully calibrated inhibition of OTULIN can 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 investigating the reasons behind the reduced levels of OTULIN long noncoding RNA in Alzheimer’s neurons and whether restoring its levels could normalize OTULIN protein expression and tau pathology.
The potential of OTULIN as a therapeutic target represents a promising avenue for future research and treatment in the ongoing fight against Alzheimer’s disease and related neurodegenerative disorders.
