A faulty neuronal skeleton—microtubules that act as scaffolding and transport tracks inside brain cells—is linked to epilepsy, intellectual disability, schizophrenia, and neurodegenerative diseases like ALS. Yet no one knows exactly how these microscopic building blocks are assembled or how their breakdown triggers disease. This project uses electron microscopy to determine the three-dimensional structure of microtubules in neurons. By comparing healthy structures with those carrying defects identified in patient DNA, the team will pinpoint where disease-causing faults occur in the machinery. That knowledge is currently missing: we understand that cytoskeleton failure is bad, but not which specific component fails or why. The research is fundamental science. There is no immediate clinical application. But knowing the precise shape and assembly rules of microtubule components could eventually allow researchers to design molecules that stabilise or repair the broken parts of the cytoskeleton. In the long term, that might lead to treatments that slow dementia, aid recovery after stroke, or repair damage from physical injury to the nervous system.
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Our brains are built from billions of specialised cells called neurons. The many complex tasks that our brains perform, including memory and thought, occur because neurons make connections with each other that allow them to communicate. Early in brain development, immature neurons are not connected to each other and must navigate to exactly the right position to correctly integrate into the brain's communication network. Healthy brain function throughout our lives depends on the connections between our neurons being well maintained. Severe human diseases can occur if neuron connectivity and operation breaks down at any stage: inaccurate neuron movement during brain development can cause epilepsy, intellectual disability and early death; incomplete maintenance of neuronal function as our brains mature into adulthood can cause neuropsychiatric illnesses including schizophrenia and mood disorders; and breakdown of neuronal function as we age can cause neurodegenerative disorders including amyotrophic lateral sclerosis and peripheral neuropathies. Work in my lab is seeking to understand the machinery that supports neuronal health during development and as we mature. In the same way as our body has a skeleton that provides us with support and strength, neurons have a skeleton - called the cytoskeleton - which also gives them support and strength. The cytoskeleton is involved in many important aspects of neuronal life, and is part of the machinery that drives movement during development and maintenance of connectivity and signaling in mature neurons. Breakdown of the neuronal cytoskeleton is associated with developmental syndromes, neurodegenerative diseases and neuropsychiatric illness. Studying the cytoskeleton machinery is important so we can understand both how healthy neurons operate and how machinery malfunction causes disease. This project will focus on a part of the cytoskeleton called microtubules. These are long cylindrical structures that act like scaffolding inside the neuron and also act as tracks along which molecular transport motors carry cargo within the neuron. The particular type of scaffolding and the particular type of cargo that is carried defines how the neuron functions. We would like to understand how the building blocks of this machinery are put together to help neurons undertake their many complex tasks within the brain. My research team studies the three-dimensional structure of microtubules, because knowing what they look like can help us understand how they work. We use a very powerful microscope called an electron microscope to take pictures of individual microtubules and then use computers to combine these pictures to calculate their three-dimensional shape. Using information from patients with diseases of the microtubule machinery, we will be able to locate disease-causing defects to particular machinery components. In the future, this knowledge may allow us to target and repair the broken parts of the cytoskeleton machinery in diseased or damaged neurons. This could allow alleviation of symptoms associated with dementia, stroke and physical injury.
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