Scientists have discovered how the brain consolidates memories. The research lasted 20 years.

 

“After many years of research on memory, scientists from the Stowers Institute have presented evidence of the deliberate creation of amyloids by the nervous system. The results may change the understanding of memory mechanisms and neurodegenerative diseases.

 

The mechanism of memory consolidation and decay has fascinated scientists for over a century.

 

The latest study conducted by a team from the Stowers Institute in the United States proves that the brain can consciously create amyloids to transform sensory experiences into lasting memory traces.

 

The results of the study, published in the "Proceedings of the National Academy of Sciences," are the culmination of over 20 years of research, providing the first direct evidence of such a process in the nervous system. This means that previous views on amyloids and their role in brain health require verification.

A new role for amyloids. What did the researchers discover?

 

For years, amyloids have been mainly associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, or Huntington's disease. They form very stable protein fibers that destroy brain cells and lead to memory loss. However, the team's research shows that amyloids can also perform another function. It turns out that they do not always have a harmful effect, but can also serve as tools that the brain uses to store information.

 

How did the scientists reach these conclusions? By focusing on chaperone proteins in the fruit fly. Until now, they were mainly attributed a protective function towards other proteins, preventing their incorrect folding. However, the study revealed the existence of a special type of chaperone protein that works somewhat differently – it enables the reshaping of proteins and the formation of functional amyloids responsible for consolidating memories. This new type of protein has been named Funes [1].

 

A new perspective on nervous system diseases

 

The experiments conducted by the researchers involved manipulating the levels of several chaperone proteins in brain areas responsible for memory. Fruit flies were trained to associate an unpleasant odor with a sugar reward. Individuals with higher levels of Funes were able to remember this association even after 24 hours. Conversely, when the scientists modified the Funes variants so that they did not trigger amyloid formation, long-term memory did not develop. This showed that Funes is an essential element in the process of memory consolidation. Preliminary results suggest that a similar mechanism may also occur in vertebrates, and perhaps is universal.

 

For years, amyloids have been mainly associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, or Huntington's disease.

 

Research into functional amyloids dates back to 2003, when a team discovered their presence in a sea slug. In subsequent years, the work was extended to organisms with more complex nervous systems, such as fruit flies, mice, and even humans. Ultimately, it was shown that the amyloid-based mechanism is widely used in memory consolidation.

 

The results of the team's work open up new avenues of research into neurodegenerative diseases. "The discovery of this chaperone protein potentially provides a new approach to amyloid-related diseases," said Kausik Si, one of the authors of the study. "It is possible that by activating these chaperones, we can reduce the toxicity of amyloids." It is also possible to increase the brain's ability to create functional amyloids, which could counteract disease-causing amyloids," he added."

 

1. Funes is a recently identified J-domain chaperone protein (CG10375) in fruit flies that facilitates the formation of long-term memories by promoting the assembly of translationally active amyloids [2]. Located within specific neural circuits, Funes stabilizes memory traces by regulating the solubility of proteins like Orb2, with higher levels improving memory retention.

 

Key Details on Funes and the Nervous System:

 

    Memory Function: Funes acts as a memory-promoting chaperone induced by neuronal activity to facilitate the transformation of specific protein complexes required for long-term memory. Funes assists in converting sensory input into long-term memory, acting at the junction where sensory stimuli converge.

 

    Mechanism of Action: Unlike most chaperones that prevent protein aggregation, Funes (a type III JDP) promotes the formation of functional amyloid aggregates of the mRNA-binding protein Orb2, which is critical for maintaining memory.

 

    Discovery: The protein was named after Jorge Luis Borges' character Funes the Memorious, due to its role in strengthening memory.

 

    Impact of Impairment: When Funes is functionally impaired, long-term memory formation is reduced.

 

    Potential Conservation: Research suggests this mechanism of memory stabilization via specialized chaperones may be conserved across species, potentially including mammals.

 

The identification of Funes highlights that the nervous system uses specific chaperone proteins to regulate memory consolidation through protein modification.

 

2. Translationally active amyloids are functional, regulated, and reversible protein aggregates with cross-𝛽 sheet structures that facilitate, rather than hinder, protein synthesis or mRNA control.

 

Unlike disease-related amyloids, these assemblies (e.g., Orb2 for memory, Rim4 for meiosis) operate as hubs for local nuclear translation or translational repression during stress and development. 

 

Key Aspects of Translationally Active Amyloids 

• Function in Memory and Development: The RNA-binding protein Orb2 forms amyloid-like, translationally active structures in the brain crucial for long-term memory.

 

• Similarly, the protein Rim4 in yeast converts into an amyloid-like aggregate to suppress translation of specific mRNAs (𝐶𝐿𝐵3) during gametogenesis.

 

• Local Nuclear Translation under Stress: Solid-like "amyloid bodies" have been found to act as sites of local nuclear protein synthesis (LNPS) during stress conditions like heat shock. These structures accumulate ribosomes, translation factors, and mRNA, functioning as specialized, organized compartments.

 

 

• Reversible Assemblies: Unlike pathological amyloids (e.g., Alzheimer's plaque), translationally active amyloids are often developmentally or metabolically regulated, forming and degrading when necessary, such as the dissolution of Rim4 aggregates at the onset of meiosis II.

Structural Characteristics: They are characterized by a core, often with cross-𝛽 sheet quaternary structure, but with unique, functional properties that distinguish them from cytotoxic amyloid aggregates. Cross-𝛽 sheet quaternary structure defines the supramolecular assembly of amyloid fibrils, where 𝛽-strands run perpendicular to the fibril axis, forming extended, stacked 𝛽-sheets. This structure, common in Alzheimer's amyloid-β and other protein aggregates, consists of two or more protofilaments (2–5 nm diameter) twisted together. The core is stabilized by interstrand hydrogen bonds (4.7 Å apart) and inter-sheet interactions (10 Å spacing). These structures are notoriously stable, often exhibiting high resistance to denaturation and proteolysis due to the extensive intermolecular hydrogen bonding network and tightly packed hydrophobic core.

 

Examples 

• Orb2: Promotes memory through the formation of an amyloid-like state that influences translation.
• Rim4: Acts as an amyloid-like translational repressor in yeast, with its aggregated form being the active state.
• Amyloid Bodies: Structures that form in the nucleus during stress (e.g., acidosis, hypoxia) and serve as localized translation hubs. 

These, and other functional amyloids, highlight that the amyloid fold is a versatile, functional mechanism, not exclusively associated with disease.