A new study in Genomic Psychiatry reports that the deubiquitinase OTULIN shapes tau production by altering gene expression and RNA metabolism, shifting current thinking about how neurons manage pathological tau. The work draws on CRISPR-edited human neuroblastoma cells and induced pluripotent stem cell-derived neurons from a patient with late-onset sporadic Alzheimer’s disease.
The team, led by Kiran Bhaskar at the University of New Mexico Health Sciences Center and Francesca-Fang Liao at the University of Tennessee Health Science Center, initially examined whether stabilizing linear ubiquitin chains would support clearance of tau aggregates. “We set out to test whether stabilizing a specific type of ubiquitin chain would help clear toxic tau from neurons,” Bhaskar said. “Instead, we discovered something completely unexpected, that OTULIN acts as a master switch controlling whether tau is even produced in the first place.”
Complete OTULIN loss caused tau mRNA to disappear. RNA sequencing showed widespread transcriptional changes, with more than 13,000 genes downregulated in OTULIN-deficient cells. Transcript-level analysis showed even broader effects, with more than 43,000 RNA transcripts downregulated and over 1,100 upregulated. Liao noted, “We found that OTULIN deficiency causes tau mRNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression.”
Alzheimer’s patient-derived neurons displayed elevated OTULIN protein and increased phosphorylated tau compared with controls. Comparison of patient-derived neurons with healthy controls revealed more than 4,500 differentially expressed genes and more than 5,600 altered transcripts. Partial pharmacologic inhibition using the small-molecule UC495 reduced phosphorylated tau without eliminating total tau. Transcriptome data indicated increased expression of RNA degradation factors such as the CCR4-NOT complex and shifts in RNA-binding ubiquitin ligases including RC3H2 and MEX3C. OTULIN long noncoding RNA was significantly reduced in patient neurons, accompanied by decreased expression of several MAGE family members. The study also identified altered expression of transcriptional regulators such as YY1 and SP3, along with shifts in RNA-binding proteins linked to neurodegeneration, including TDP-43, FMR1, ATXN2, and MSI1. OTULIN loss also reduced expression of inflammatory pathway components, which prevented autoinflammatory signaling in neurons.
The research team is now mapping the molecular steps linking OTULIN to RNA metabolism and evaluating calibrated OTULIN inhibition in animal models. They are also assessing how OTULIN long noncoding RNA contributes to OTULIN protein levels and tau pathology.
Publication Details
Tangavelou K, Bondu V, Li M, Li W, Liao F, Bhaskar K. The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons. Genomic Psychiatry. Published online 25 November 2025. doi: 10.61373/gp025a.0116
The team, led by Kiran Bhaskar at the University of New Mexico Health Sciences Center and Francesca-Fang Liao at the University of Tennessee Health Science Center, initially examined whether stabilizing linear ubiquitin chains would support clearance of tau aggregates. “We set out to test whether stabilizing a specific type of ubiquitin chain would help clear toxic tau from neurons,” Bhaskar said. “Instead, we discovered something completely unexpected, that OTULIN acts as a master switch controlling whether tau is even produced in the first place.”
Complete OTULIN loss caused tau mRNA to disappear. RNA sequencing showed widespread transcriptional changes, with more than 13,000 genes downregulated in OTULIN-deficient cells. Transcript-level analysis showed even broader effects, with more than 43,000 RNA transcripts downregulated and over 1,100 upregulated. Liao noted, “We found that OTULIN deficiency causes tau mRNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression.”
Alzheimer’s patient-derived neurons displayed elevated OTULIN protein and increased phosphorylated tau compared with controls. Comparison of patient-derived neurons with healthy controls revealed more than 4,500 differentially expressed genes and more than 5,600 altered transcripts. Partial pharmacologic inhibition using the small-molecule UC495 reduced phosphorylated tau without eliminating total tau. Transcriptome data indicated increased expression of RNA degradation factors such as the CCR4-NOT complex and shifts in RNA-binding ubiquitin ligases including RC3H2 and MEX3C. OTULIN long noncoding RNA was significantly reduced in patient neurons, accompanied by decreased expression of several MAGE family members. The study also identified altered expression of transcriptional regulators such as YY1 and SP3, along with shifts in RNA-binding proteins linked to neurodegeneration, including TDP-43, FMR1, ATXN2, and MSI1. OTULIN loss also reduced expression of inflammatory pathway components, which prevented autoinflammatory signaling in neurons.
The research team is now mapping the molecular steps linking OTULIN to RNA metabolism and evaluating calibrated OTULIN inhibition in animal models. They are also assessing how OTULIN long noncoding RNA contributes to OTULIN protein levels and tau pathology.
Publication Details
Tangavelou K, Bondu V, Li M, Li W, Liao F, Bhaskar K. The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons. Genomic Psychiatry. Published online 25 November 2025. doi: 10.61373/gp025a.0116