How dementia proteins become dysfunctional
Image: Signalling protein Fyn moving and forming clusters in living brain cells. [Meunier Lab, University of Queensland]
Australia-based researchers have used super-resolution microscopy to observe key molecules at work inside living brain cells, shedding new light on memory formation and the causes of dementia.
Professors Frédéric Meunier and Jürgen Götz from the University of Queensland Brain Institute discovered how the Alzheimer's Tau protein affects the organisation of signalling protein, Fyn, which plays a critical role in memory formation.
"One of the distinguishing features of Alzheimer's disease is the tangles of Tau protein that form inside brain cells,” says Götz. “But this is the first time anyone has demonstrated that Fyn nanoclustering is affected by Tau."
According to the researchers, single molecule imaging in living brain cells allows unprecedented access to the organisation of key proteins in small nanoclusters that have not been detectable.
"We have shown that Tau controls the Fyn nanoclustering in dendrites, where the communication between brain cells occurs," highlights Meunier. "When Tau is mutated, Fyn makes aberrantly large clusters, thereby altering nerve signals and contributing to dysfunction of the synapse-junctions between nerve cells."
Meunier and colleagues used single-particle tracking photoactivated localization microscopy (sptPALM) to see how Tau and its mutants control Fyn nanoclustering.
They also investigated a different mutant of Tau, which is found in families with a high risk of developing frontotemporal dementia, discovering that Fyn was over-clustered in the spines of dendrites.
"Imagine that you have clustering of Fyn, a signalling molecule, throughout your life; it's going to give rise to an over-signalling problem,” says Meunier. “This could be one of the ways in which Fyn is toxic to cells.”
"The spines of the dendrites are critical to how nerve cells communicate with each other and underpin memory and learning," he adds.
Exactly what causes Alzheimer's and other forms of dementia is still a mystery, but Fyn is linked to both the plaques of amyloid protein that form between brain cells as well as the tangles of Tau protein that form inside brain cells; two key features of Alzheimer's disease.
"Super-resolution single molecule imaging gives us unprecedented insights into what is happening in living nerve cells, with the aim of understanding the biology behind these complex and debilitating diseases," concludes Meunier.
Research is published in eLife.