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Scientists have removed a toxic brain protein from human neurons, and the cells showed no obvious signs of distress afterward.
That cleanup connects an immune-related enzyme to both brain inflammation and aging, putting dementia research on a sharper track.
Neurons, stem cells, and OTULIN
In human neurons grown from stem cells, disabling OTULIN, an enzyme that helps control inflammation signals, erased the toxic protein.
At the University of New Mexico (UNM), Karthikeyan Tangavelou, Ph.D., tested cells from two sources and watched the toxic protein fade.
Using neurons derived from an Alzheimer’s donor and a common neuroblastoma cell line, Tangavelou saw the effect in both at UNM.
Even so, the finding points back to the protein’s normal job, which starts out helpful before it turns harmful.
Tau and tangles
During normal brain function, tau, a protein that steadies internal transport tracks, helps neurons keep their long extensions organized.
After extra chemical tags build up, phosphorylation, a change that adds phosphate groups to proteins, can make tau clump inside cells.
Over time, neurofibrillary tangles, twisted bundles of tau that crowd cells, appear in Alzheimer’s disease and more than 20 others.
Because these tangles rise as disease progresses, scientists have hunted for ways to stop tau at its source.
OTULIN’s surprise job
For years, OTULIN appeared mainly in immune studies, where it helped stop inflammatory alarms from running out of control.
By slicing off ubiquitin, a small tag that steers protein fate, OTULIN can calm stress signals and limit cell death.
Instead of only cleaning up proteins, the new results tie OTULIN to RNA metabolism, the steps that make and erase gene messages.
That surprise means a drug could cut tau production upstream, but it also risks disturbing other genes the same way.
Two ways to target
With one strategy, the team used a custom small molecule, UC495, to slow OTULIN without deleting it.
In donor-derived neurons, the blocker cut levels of the protein carrying extra phosphate tags, while overall amounts changed little.
Deleting the OTULIN gene went further and wiped it out at both the gene-message stage and the protein stage.
Such a gap between slowing and deleting OTULIN hints that any future therapy may need fine control, not brute force.
Living without tau
After the edit, the neurons kept their usual look in culture, instead of showing signs of injury or stress.
Markers of neuron survival stayed steady, and a basic identity signal did not drop when the OTULIN gene was removed.
Neurons appeared to survive without tau, the researchers reported after completing the experiments. Still, removing tau from a dish is not the same as clearing it from a living brain, where many cell types interact.
The message vanishes
When the team blocked major protein-disposal pathways, the protein still stayed gone, ruling out simple overactive cleanup.
Instead, its disappearance began earlier, at the level of messenger RNA, the short-lived text copied from genes, in OTULIN-free cells.
Without that message, the tau-making gene could not supply fresh protein, so the cell had nothing to clear.
This puts OTULIN in an awkward spot as a drug target, because changing RNA control can ripple far beyond tau.
Genes change at scale
Across the genome, losing OTULIN rewrote the cell’s normal program, not just the part tied to tau.
Using RNA sequencing, a method that counts gene messages at once, the team saw 13,341 genes drop in a neuroblastoma cell line.
“We believe that OTULIN is the master regulator of brain aging, because this protein regulates RNA metabolism,” said Tangavelou.
Many of the biggest drops hit inflammation-related genes, which may protect neurons but also makes the biology harder to control.
Aging signals and risk
In aging brains, neurons struggle to keep protein making and protein disposal balanced, and OTULIN now sits near that control point.
Outside neurons, OTULIN defects cause autoinflammatory syndrome, an immune-driven illness that flares without infection, in some patients.
Brain support cells, including microglia, immune-like cells that patrol brain tissue, may react very differently if OTULIN disappears there.
“If there is no OTULIN in microglia, that may cause auto-inflammation,” said Tangavelou, describing a key safety concern.
Future of OTULIN
Drug developers now face a tempting goal, dial down OTULIN in neurons enough to curb tau without rewiring other genes.
Careful dosing with small molecules may offer that middle ground, while gene deletion looks too blunt for a whole brain.
Animal studies will need to watch memory, movement, and immune signaling at the same time, since OTULIN touches RNA control.
If that balance holds, the work could support tau-focused treatments that start earlier, before tangles spread through the brain.
By linking an immune enzyme to the very making of tau, the study reframes what it means to clear a neuron.
Future work must prove the same approach stays safe in animals and in other brain cells, not just neurons grown in dishes.
The study is published in Genomic Psychiatry.
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