Cleaning Up Toxic “Protein Clumps” Could Prevent Dementia

Sparking Learning and Memory

Recent research from the University of Queensland suggests that clearing out cellular “protein clumps” may prevent the onset of certain forms of dementia.

The Queensland Brain Institute researchers made the finding after studying the link between the enzyme Fyn and the protein Tau in frontotemporal dementia.

The research team, led by Professor Frederic Meunier and Dr. Ramón Martnez-Mármol, discovered that Fyn, a key aspect of memory and learning, becomes extremely active when immobilized inside synapses, the connection hubs between neurons where neuronal communication takes place.

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“Using super-resolution microscopy, we can now see these enzymes individually and in real-time, moving around randomly in live neurons,” Lead author Dr. Martínez-Mármol said.

The research team discovered that when these enzymes are activated, they transform into an opened structure (similar to a flower that blossoms) and slow down their movement. They then cluster or form clumps of proteins before refolding and dispersing to begin their cycle again.

“When they need to complete an action, the Fyn enzymes slow down and congregate at the synapse to initiate their function,” Dr. Martínez-Mármol said.

Trajectory map of individual Fyn molecules in hippocampal neurons. Credit: Queensland Brain Institute

Protein clusters key for learning and memory

This process naturally occurs thousands of times at the synapses between neurons and is required to sustain neuronal communication, which is the basis of learning and memory. Professor Frederic Meunier explained that Fyn must form these dynamic clusters in order for learning and memory to occur.

“But if you alter the balance in any way – you have too little, or too much clustering, you develop pathological issues,” Professor Meunier said.

The research follows the team’s earlier work, where they discovered Tau impacted a critical mechanism in memory function.

Fyn trajectories forming in a hippocampal dendritic spine. The cluster of Fyn is an important process of learning and memory but when associated with Tau, can become the precursor to dementia. Credit: University of Queensland

The team showed, using super-resolution microscopy, that when neurons are exposed to a mutant version of Tau present in frontotemporal dementia, the clustering of the Fyn enzyme is accentuated with the potential to trigger a debilitating chain reaction.

The association of Fyn and Tau necessary for the progression of different forms of dementia, including Alzheimer’s disease and frontotemporal dementia, has been demonstrated by many laboratories around the world; however, the precise molecular mechanisms behind this pathological interaction were not known.

Toxic Tau creates a dementia spider web

Importantly, this mutant Tau has a higher propensity to form what is known as biomolecular condensates, which are small gel-like droplets within the cells. Some proteins, under specific conditions, tend to spontaneously aggregate, forming droplets that resemble oil spills in an aqueous solution. Tau is one of these proteins.

Dr. Ramón Martínez-Mármol. Credit: Queensland Brain Institute

If formed at the neuronal synapses, these Tau droplets create the perfect trap for Fyn molecules, keeping them highly immobile and accentuating their clustering and activation for longer.

“It’s like a spider web,” Dr. Martínez-Mármol said. “Normally, Fyn stops and moves, stops and moves

“In frontotemporal dementia, Fyn stops more as it becomes stuck in this gel-like structure. The droplets of Tau, therefore, attract additional Fyn proteins at the synapse.”

Professor Meunier said Tau biomolecular condensates could hold the key to reverting this toxic chain reaction.

“We believe they are the perfect target for future therapy to re-establish normal Fyn clustering dynamics,” Professor Meunier said.

“Theoretically, attacking the formation of toxic Tau biomolecular condensates should prevent the process of dementia from happening.”

Reference: “Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates” by Ramón Martínez-Mármol, Christopher Small, Anmin Jiang, Tishila Palliyaguru, Tristan P. Wallis, Rachel S. Gormal, Jean-Baptiste Sibarita, Jürgen Götz, and Frédéric A. Meunier, 18 October 2022, Molecular Psychiatry.
DOI: 10.1038/s41380-022-01825-y\

The study was funded by the National Health and Medical Research Council.