Cleaning Up Toxic “Protein Clumps” Could Prevent Dementia

Neuroscience Brain Mapping Confusion Dementia

Dementia is a broad time period that refers back to the impaired skill to recollect, suppose, or make choices.

Sparking Studying and Reminiscence

Latest analysis from the College of Queensland means that clearing out mobile “protein clumps” might stop the onset of sure types of dementia.

The Queensland Mind Institute researchers made the discovering after learning the hyperlink between the enzyme Fyn and the protein Tau in frontotemporal dementia.

The analysis crew, led by Professor Frederic Meunier and Dr. Ramón Martnez-Mármol, found that Fyn, a key side of reminiscence and studying, turns into extraordinarily lively when immobilized inside synapses, the connection hubs between neurons the place neuronal communication takes place.

“Utilizing super-resolution microscopy, we will now see these enzymes individually and in real-time, shifting round randomly in dwell neurons,” Lead creator Dr. Martínez-Mármol stated.

The analysis crew found that when these enzymes are activated, they rework into an opened construction (just like a flower that blossoms) and decelerate their motion. They then cluster or type clumps of proteins earlier than refolding and dispersing to start their cycle once more.

“When they should full an motion, the Fyn enzymes decelerate and congregate on the synapse to provoke their perform,” Dr. Martínez-Mármol stated.

Fyn Molecules

Trajectory map of particular person Fyn molecules in hippocampal neurons. Credit score: Queensland Mind Institute

Protein clusters key for studying and reminiscence

This course of naturally happens 1000’s of occasions on the synapses between neurons and is required to maintain neuronal communication, which is the premise of studying and reminiscence. Professor Frederic Meunier defined that Fyn should type these dynamic clusters to ensure that studying and reminiscence to happen.

“However in case you alter the stability in any approach – you’ve gotten too little, or an excessive amount of clustering, you develop pathological points,” Professor Meunier stated.

The analysis follows the crew’s earlier work, the place they found Tau impacted a essential mechanism in reminiscence perform.

Fyn trajectories forming in a hippocampal dendritic backbone. The cluster of Fyn is a vital strategy of studying and reminiscence however when related to Tau, can grow to be the precursor to dementia. Credit score: College of Queensland

The crew confirmed, utilizing super-resolution microscopy, that when neurons are uncovered to a mutant model of Tau current in frontotemporal dementia, the clustering of the Fyn enzyme is accentuated with the potential to set off a debilitating chain response.

The affiliation of Fyn and Tau crucial for the development of various types of dementia, together with 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.

Ramon Martinez Marmol

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.

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