Even though researchers have been studying the tau protein for decades, the molecular mechanisms by which tau contributes to Alzheimer’s disease and other forms of dementia are still not fully understood. Frederic Meunier, a neurobiologist at the University of Queensland, thinks that some of tau’s toxicity relates to its interactions with an enzyme called Fyn.

“Fyn is a very important enzyme,” said Meunier. “It’s linked to memory in many different ways." Fyn also seems to play a role in Alzheimer’s disease (1).

Under normal circumstances, Fyn moves around inside a neuron quite quickly. “If Fyn was the size of a person, it would travel about 250 kilometers per hour, just bouncing everywhere,” said Meunier. However, Fyn can also cluster in the postsynaptic regions of neurons. Meunier wanted to understand the molecular factors that allowed this fast-moving enzyme to accumulate in such small, specific regions of the neuron, as well as how tau affects the movement of Fyn enzymes at the nanoscale level.

Fyn is a very important enzyme. It’s linked to memory in many different ways. 
- Frederic Meunier, the University of Queensland

In order to answer these questions, Meunier and Ramón Martínez-Mármol, a research fellow at the University of Queensland, used super-resolution microscopy to track individual Fyn proteins as they bounced around inside cultured hippocampal neurons (2).

In normal neurons, they found that when Fyn switched from a tight, closed shape to a more open form, it promoted Fyn clustering in the dendrites. When the neurons expressed a mutant form of the tau protein that associates with dementia, however, Fyn clustering increased above normal levels.

The team then investigated the mechanisms through which tau caused this abnormal clustering. Previous work showed that tau can form biomolecular condensates, or membraneless droplets, inside the cell; the mutant form of tau has an even higher likelihood of forming these condensates (3). The team thought that these mutant tau droplets might sequester Fyn enzymes, trapping them together and resulting in the abnormally high clustering. And indeed, said Meunier, “we showed that if you dissolve this biomolecular condensate, this extra clustering is gone.”

This is important because while a certain level of Fyn seems to be required for learning and memory, hyperactivity of Fyn can be toxic, contributing to neuronal dysfunction and death in dementia (1). By targeting tau biomolecular condensates, researchers might be able to bring Fyn clustering back down to normal levels, which might help treat or prevent some forms of dementia.

While there’s still a lot of work to be done, “we think that there's definitely some scope here to design drugs,” said Meunier.

References

1. Nygaard, H. B., van Dyck, C. H. & Strittmatter, S. M. Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alz Res Therapy  6, 8 (2014).
2. Martínez-Mármol, R. et al. Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates. Mol Psychiatry  28, 946–962 (2023).
3. Kanaan, N. M., Hamel, C., Grabinski, T. & Combs, B. Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nat Commun  11, 2809 (2020).