Trajectory map of individual Fyn molecules in hippocampal neurons. Credit: Queensland Brain Institute
Fyn is an enzyme that plays a key role in learning and memory, which functions by dynamically forming nanoclusters at neuronal synapses. Previous research has established that interactions between Fyn and a mutant version of the protein Tau contribute to different forms of dementia, including Alzheimer’s disease and frontotemporal dementia; however, the precise molecular mechanisms behind this pathological interaction were not known. Now, researchers from the Queensland Brain Institute have used super-resolution microscopy to uncover the details of Fyn’s clustering behavior and interactions with Tau, which could lead to new therapeutic strategies for preventing dysfunction that leads to dementia.
The team observed the behavior of Fyn using single-particle tracking photoactivated localization microscopy (sptPALM), a technique that allowed them to track individual enzymes in real time as they moved around living neurons, said lead author Ramón Martínez-Mármol. They found that when the enzyme became activated, it changed its form from a closed to an open structure, which caused it to slow down and group together into nanoclusters at the synapse. A dynamic cycle of opening and closing, clustering and dispersing, is necessary to maintain normal neuronal communication, which is the basis of learning and memory. A disruption in the balance – such as too much or not enough clustering of Fyn – can impact neuronal function and contribute to dementia, said corresponding author Frederic Meunier.
By exposing neurons to the mutant version of Tau present in frontotemporal dementia, and observing the proteins and enzymes using sptPALM, the researchers could see how Tau impacted the clustering behavior of Fyn at the synapses. The mutant form of Tau has a higher propensity to form biomolecular condensates – small, gel-like droplets within the cells – and at synapses, these droplets can trap Fyn, accentuating its clustering and keeping it activated for longer, the researchers found. This immobilization and buildup of Fyn due to the gel-like Tau condensates is a “toxic chain reaction” that impairs brain function in frontotemporal dementia, according to the researchers. “Clean-up” of these droplets to avoid this chain reaction is a potential strategy for protecting neurons from dysfunction. This study was published in Molecular Psychiatry.
“We believe they are the perfect target for future therapy to re-establish normal Fryn clustering dynamics,” said Meunier. “Theoretically, attacking the formation of toxic Tau biomolecular condensates should prevent the process of dementia from happening.”