Watch Prof Frédéric Meunier and Dr Shanley Longfield accept the research grant award and hear a bit about the project.
Project Summary:
One critical step in the pathological journey of a Tau molecule harbouring a frontotemporal dementia (FTD) mutation is the generation of aggregates in neurons, leading to neurodegeneration that affects memory, language, and behaviour. How mutated Tau becomes toxic and disrupts normal brain communication leading to cognitive decline and brain cell loss is currently unknown.
For the first time, we will harness state-of-the-art single molecule super-resolution microscopy to track Tau molecules in a living neuron as they start their pathological journey. One of our recent discoveries shows that non mutated Tau forms small droplets which help control communication between neurons. This function is crucial for memory formation and normal brain activity. However, when this process goes awry, it can contribute to diseases like FTD. Our hypothesis is that the formation and maintenance of these droplets is affected and lead to long-lasting toxic aggregates.
Our research aims to investigate how Tau FTD mutation affects its behaviour at the nanoscale level, focusing on its impact on the movement of synaptic vesicle containing neurotransmitters, essential for neuronal communication. Further, we will uncover how Tau becomes dysfunctional at the nanoscale level and how it contributes to the progression of FTD. By visualising these processes in unprecedented detail, it would provide crucial insights into how FTD develops and pave the way for future treatments. Our ultimate goal is to use this knowledge to develop new therapies that could slow or prevent the progression of FTD, improving the lives of those affected by this devastating condition.
Outcomes
In this project, Dr Longfield and Prof Meunier investigated an inherited mutation linked to a severe neurodegenerative form of FTD, called TauP301S. They used advanced single-molecule imaging to measure the movement and behaviour of the mutated Tau compared to normal Tau. They were also interested in how the mutation affected recycling synaptic vesicles – a part of the neuron that contains neurotransmitters, and is key for communication between neurons.
Their findings revealed that the mutation did not significantly affect the location or movement of Tau proteins. The mutated Tau also did not have a clear response to electrical or chemical stimulation. This suggests that TauP301S does not measurably alter the displacement of individual Tau molecules, but could still alter higher-order organisation.
A key discovery was that this mutation significantly increased the mobility of recycling synaptic vesicles, specifically within the axons rather than the presynaptic terminals. This points to axons as an important site where disease-related changes may begin. Axons are crucial pathways for a number of reasons, so changes in axonal organisation and transport can affect synapses indirectly – even when Tau itself is not strongly concentrated at the presynaptic terminals.
These findings are an important step towards understanding the role of Tau mutation in FTD, and provide a strong basis for future research.
Outcomes submitted March 2026.
The Brain Foundation is dedicated to funding the next generation of Australian research into brain disorders, diseases, and injuries, with the ultimate goal of advancing diagnoses, treatments, and patient outcomes.