Set to publish in the Proceedings of the National Academy of Sciences on January 30, 2026, the study from the Si Lab focuses on "chaperone proteins" in the fruit fly. Chaperones guide other proteins to attain the correct folded state. In the nervous system, they have long been thought to either help proteins fold correctly or prevent harmful misfolding and clumping. But the researchers discovered a specific type of chaperone that does something unexpected — it allows proteins to change their shape and form functional amyloids that house long-term memory.

“This expands the idea of a protein’s capacity to do meaningful things, and suggests there is an unknown universe of chaperone biology that we’ve long been missing,” Si said.

Amyloids are typically associated with neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinsons. They form tightly packed, highly stable “detrimental” protein fibers that destroy brain cells, erasing the memories of their host.

The new research not only strengthens the Si Lab’s paradigm-shifting 2020 Science study which explained amyloids are not always harmful, unregulated byproducts as previously thought; it also proves amyloids can be carefully controlled — serving as tools the brain uses to store information. Ultimately, the research reveals for the first time a critical step in the process of how long-lasting memories endure.

"Discovering this chaperone protein has now provided us with an avenue to potentially approach amyloid-based diseases in an unanticipated way,” Si said. “It may be possible to either activate these chaperones and guide toxic amyloids to be less harmful — or, by activating them, we can potentially endow the brain with enhanced capacity to form functional amyloids. This could then override the intrusion of disease-causing amyloids.”

Tackling a century-old question

The Si Lab knew from their 2020 study, led by former Stowers Postdoctoral Research Associate Rubén Hervas, Ph.D., now an Professor at the University of Hong Kong and co-corresponding author on the current study, that the formation of amyloids can allow animals to form stable memories.

"But we did not know how or when,” Si said.

“The fact that amyloid is needed to form memory implied there must be a mechanism that controls the process,” Hervas said. The researchers hoped that if they could identify the mechanism, they could also manipulate it in a meaningful manner to influence memory.

“Despite 100 years of studying amyloid biology, nobody has ever asked how the brain can deploy amyloid,” Si explained. “Because amyloid formation was historically thought to be unintentional and unintended, it was now necessary for us to ask that question.”

A pivotal discovery that led to identifying the chaperone

In 2003, Si first discovered the existence of a functional amyloid in the sea slug. With just 10,000 neurons, this simplified system was a first but pivotal step toward rethinking amyloid biology. His lab then expanded the research to more complex animals including fruit flies (~150,000 neurons), mice (70-80 million neurons), and even humans (~86 billion neurons). The team eventually uncovered that an amyloid-based mechanism is broadly used for memory persistence.

In fruit flies, a prion-like protein called Orb2 (and its relative protein CPEB in mammals) must undergo self-assembly at the synapses, the gap between two neurons, to maintain a memory. Over time, the researchers began to hypothesize that the difference between a harmful and a helpful amyloid may depend on whether Orb2’s assembly process is tightly regulated by other proteins.

This new study allowed the team to finally test that hypothesis. To find the regulator, they investigated a family of chaperones that manage protein behavior in neurons and, using an associative memory model, they identified a previously uncharacterized chaperone.

“We were inspired by Jorge Luis Borges’ short story Funes the Memorious in which one man’s perfect memory comes at a cost, so we named the chaperone Funes,” said Kyle Patton, Ph.D., a former Stowers Graduate School student and lead author on the study.

Finding Funes

The researchers discovered Funes by manipulating the concentrations of 30 different chaperones in the fly’s memory centers.

“We trained very hungry fruit flies to link a specific, unpleasant smell with a sugar reward,” Patton said. Flies with increased levels of Funes showed a remarkable ability to remember the odor-reward link after 24 hours — a standard proxy for long-term memory.

But the most surprising discovery came at the molecular level. At his lab in Hong Kong, Hervas engineered Funes variants that could bind Orb2 but could not trigger its transition into amyloid, and found the flies’ long-term memory failed. This indicated that Funes is an essential component for long-term memory formation.

“We are now getting early evidence that, like the fruit fly shows in this study, the process may also be manifesting in the vertebrate nervous system,” Si said. “Our hypothesis is carrying us all the way to the vertebrate brain, illustrating that it may actually be universal.”

The biology of chaperones: New insights into brain health and disorders

While screening the chaperone proteins in fruit flies, the team made another unexpected connection that potentially broadens the study’s relevance.

Funes was the most striking, but not the only chaperone to affect memory. “If you look at the human version of these genes, they have surprisingly been implicated by genome-wide association studies in schizophrenia,” Patton said. “That’s not something we anticipated.”

Patton cautioned that the overlap does not mean schizophrenia is a “disease of chaperones,” but it opens the door to the possibility that the chaperones could be key factors, potentially acting as mediators.

“Ultimately, chaperones may allow the brain to perceive, process, or store information about the outside world,” Si said. “And in diseases where we do not see the world as it is, like schizophrenia or bipolar disorder, we could imagine chaperones playing a role.”

“While it’s an unknown universe, it’s an exciting one, and we’ll see where we end up,” Si added. “What's remarkable is that we’re now thinking about new ways to treat human diseases, and it all started by studying the sea slug, an organism that, compared to us, is relatively simple.”

Additional authors include Yangyang Yi, Ph.D., Raj Burt, Kevin K-S. Ng, Ph.D., Mayur Mukhi, and Peerzada Shariq Shaheen Khaki, Ph.D.

This work was funded by the Enhanced New Staff Start-up Research Grant from the University of Hong Kong, the Seed Fund for Basic Research from the University of Hong Kong, the Research Grant Council of Hong Kong (award: 17118624), and with institutional support from the Stowers Institute for Medical Research.

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About the Stowers Institute for Medical Research

Founded in 1994 through the generosity of Jim Stowers, founder of American Century Investments, and his wife, Virginia, the Stowers Institute for Medical Research is a non-profit, biomedical research organization with a focus on foundational research. Its mission is to expand our understanding of the secrets of life and improve life’s quality through innovative approaches to the causes, treatment, and prevention of diseases.

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