When nerve cells lose the ability to dispose of their own garbage, the consequences can be devastating. Researchers at Rockefeller University and University College London have identified mutations in the PSMF1 gene that cripple the brain's protein cleanup system, triggering a spectrum of severe neurological disorders that can strike in infancy or progress into adulthood.
The discovery centers on a transporter protein called PI31, which acts as a molecular courier shuttling proteasomes—the cell's protein-degrading machines—from the nerve cell body to synapses, where brain cells communicate with one another. Hermann Steller's team at Rockefeller has spent 15 years mapping how this system works. When PI31 malfunctions due to mutations in PSMF1, proteasomes fail to reach their destinations. Synapses become starved of their degradative capacity, and proteins that should be eliminated accumulate into clumps. The result is a cascade of failure: synaptic communication breaks down, neuronal health deteriorates, and disease takes hold.
This matters because neurodegenerative diseases like Alzheimer's and Parkinson's have confounded researchers for over a century. Scientists have long observed the protein aggregates that define these diseases—tau tangles, beta-amyloid plaques, Lewy bodies—but remain largely unable to prevent them from forming or eliminate them from the brain. Current therapies targeting these clumps have proven disappointingly ineffective at halting disease progression. The new research reframes the problem: what if the plaques are not the root cause but a symptom of something deeper—a failure of the protein disposal system itself?
A team led by Francesca Magrinelli at University College London examined the genetics of 25 individuals from 18 families of diverse ethnic backgrounds and found PSMF1 mutations linked to severe, sometimes lethal neurological disorders ranging from infancy through adulthood. To understand what these mutations do at the cellular level, Jose Rodriguez, a postdoctoral associate in Steller's lab, studied animal models and found that PI31 deficiency caused movement and behavioral problems followed by progressive neurodegeneration.
The implications are profound. Steller's 2019 research showed that knocking out the PSMF1 gene led to synaptic dysfunction and neuronal degeneration. More recently, in 2025, his team discovered that boosting PI31 in animal models can prevent neuronal degeneration and restore synaptic function—suggesting a potential therapeutic target. Rather than chasing the plaques themselves, researchers might prevent them from forming in the first place by ensuring proteasomes reach the synapses where they're needed most.
"I believe the protein aggregates that define neurodegenerative diseases are the consequence, not the primary cause," Steller says. "Therefore, increasing the activity of proteasomes at synapses should assure the removal of all unwanted proteins, and plaques will never form." This represents a fundamental shift in how scientists might approach not just rare genetic disorders tied to PSMF1 mutations, but age-related neurodegeneration affecting millions. The work opens a new avenue toward developing therapies that preserve cognitive function by fixing the system that keeps synapses clean—before damage becomes irreversible.