Removing toxic "protein clumps"

A new study from the University of Queensland shows that clearing 'protein clumps' from cells can prevent certain types of dementia from developing
.
Researchers at the Queensland Brain Institute came to this finding
after focusing on the relationship between the Fyn enzyme and the Tau protein in frontotemporal dementia.
The research team, led by Prof.
Frederic Meunier and Dr Ramón Martínez-Mármol, found that Fyn plays an important role in learning and memory, becoming highly active
when it is fixed within synapses.
Synapses are the connecting hubs between neurons, where communication between neurons takes place
.

"Using super-resolution microscopy, we can now see these enzymes moving randomly in living neurons," said
lead author Dr.
Martínez-Mármol.

The team found that when these enzymes are activated, they become an open structure (like a flowering flower) and slow their movement, clumping together to form protein clusters or clumps, which then refold and disperse, starting their cycle
again.

Dr.
Martínez-Mármol said: "When they need to complete an action, the Fyn enzyme slows down, gathers at the synapse to initiate their function
.
"

Normally, this process occurs naturally thousands of times at synapses between neurons and is necessary to maintain neuronal communication, which is the basis for
learning and memory.

Professor Meunier explains that in order for learning and memory to occur, Fyn needs to form these dynamic clusters
.
"But if you change that balance in any way — too little or too much clustering — you have pathological problems," Professor Meunier said
.

The study continues the team's earlier work, when they found a key mechanism by
which Tau proteins affect memory function.
Using super-resolution microscopy, the team showed that when neurons were exposed to a mutated version of the Tau protein in frontotemporal dementia, the aggregation of the Fyn enzyme was enhanced, potentially triggering a debilitating chain reaction
.
The link between Fyn and Tau, necessary during the development of different forms of dementia, including Alzheimer's disease and frontotemporal dementia, has been confirmed in many laboratories around the world; However, the precise molecular mechanisms behind this pathological interaction are unclear
.
Importantly, this mutant Tau protein is more likely to form so-called biomolecular condensates, which are small gel-like droplets
within cells.
Under certain conditions, some proteins tend to aggregate spontaneously, forming water droplets, similar to oil spills
in an aqueous solution.
Tau is one such protein
.

If synapses form in neurons, these Tau droplets create the perfect trap for Fyn molecules, keeping them highly immobile and emphasizing their aggregation and activation
for a longer period of time.

"It's like a spider's web," says
Dr.
Martínez-Mármol.
"Normally, Fyn stops to move, stops to move, and in frontotemporal dementia, Fyn gets more
stagnant in this gelatinous structure.
Thus, Tau protein droplets attract extra Fyn protein
at synapses.
”

Tau biomolecular agglomerates may be the key to
reversing this toxic chain reaction.
"We believe they are the perfect target for future treatments that can re-establish normal Fyn cluster dynamics," Professor Meunier said
.
"Theoretically, attacking the formation of toxic Tau biomolecular agglomerates should prevent dementia from developing
.
"

Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates