Researchers have made a significant discovery about the brain enzyme OTULIN and its unexpected role in regulating the expression of tau, a protein implicated in Alzheimer’s disease. This groundbreaking study, published in Genomic Psychiatry, reveals that OTULIN not only participates in protein degradation but also acts as a master regulator of gene expression and RNA metabolism.
The research, conducted by a 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, focused on how neurons eliminate abnormal tau aggregates. Their findings could pave the way for new therapeutic strategies for Alzheimer’s and related dementias, which affect millions globally.
Unveiling OTULIN’s Revolutionary Role
Initially, the team aimed to investigate whether stabilizing a specific type of ubiquitin chain would enhance the clearance of toxic tau from neurons. To their surprise, when they completely eliminated the OTULIN gene in neurons, tau levels dropped significantly—not due to enhanced degradation, but because the protein was not being produced at all.
“This was a paradigm shift in our thinking,” stated Dr. Liao. “We found that OTULIN deficiency leads to the disappearance of tau mRNA and causes significant changes in how the cell manages RNA and controls gene expression.”
The study utilized neurons derived from a patient with late-onset sporadic Alzheimer’s disease, revealing elevated levels of both OTULIN and phosphorylated tau compared to healthy control neurons. This correlation indicated that OTULIN might contribute to disease progression.
The research yielded several critical insights:
1. Removing OTULIN from neuroblastoma cells resulted in comprehensive RNA sequencing that showed dramatic shifts in gene expression—13,341 genes were downregulated and 774 upregulated, while RNA transcripts exhibited even more pronounced alterations (43,003 downregulated, 1,113 upregulated).
2. Inhibiting OTULIN’s enzymatic activity with a novel small molecule inhibitor, UC495, decreased phosphorylated tau levels in Alzheimer’s neurons, suggesting a potential therapeutic benefit without the complete elimination of the gene.
3. The absence of OTULIN led to the upregulation of numerous genes associated with RNA degradation and stability regulation, including components of the CCR4-NOT complex and various RNA-binding proteins, which are implicated in neurodegenerative diseases.
4. Bulk RNA sequencing of Alzheimer’s neurons showed significant downregulation of OTULIN long noncoding RNA and diminished expression of melanoma antigen gene (MAGE) family members, which activate ubiquitin ligases involved in protein quality control.
Implications for Alzheimer’s Treatment
These findings have substantial implications for treating tauopathies, a group of more than 20 neurodegenerative diseases characterized by toxic tau accumulation. “OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully instead of eliminating it entirely,” noted Dr. Bhaskar. “Complete loss leads to widespread changes in cellular RNA metabolism that could result in unintended consequences.”
The research demonstrated that partial inhibition with UC495 reduced pathological forms of tau without causing noticeable toxicity to neurons. This indicates a potential therapeutic window where OTULIN activity could be adjusted to beneficial levels. Additionally, the team found that OTULIN deficiency mitigates autoinflammation in neurons by downregulating components of inflammatory pathways, enhancing our understanding of how cells balance protein quality control and inflammatory responses.
The study also sheds light on fundamental mechanisms of RNA metabolism regulation in neurons. Researchers observed upregulation of transcriptional repressors like YY1 and SP3 in OTULIN-deficient cells, along with alterations in RNA-binding ubiquitin ligases that govern mRNA stability. “We’re essentially identifying a previously unknown checkpoint in gene expression,” explained Dr. Liao. “OTULIN seems to influence which genes are expressed and the longevity of their RNA messages within cells.”
Moreover, the study identified connections between OTULIN and multiple RNA-binding proteins linked to various neurodegenerative diseases, indicating broader implications for understanding brain disorders.
Next steps for the research team involve delving deeper into how OTULIN influences gene expression and RNA metabolism at the molecular level. They are also exploring whether carefully calibrated OTULIN inhibition can mitigate 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 if targeting OTULIN therapeutically can safely reduce tau accumulation without disrupting essential cellular functions.”
Researchers are also investigating why OTULIN long noncoding RNA levels are reduced in Alzheimer’s neurons and whether restoring these levels might normalize OTULIN protein expression and tau pathology.
The study, titled “The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons,” is set to be published in March 2025, offering an exciting new chapter in the quest for effective Alzheimer’s treatments.
