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Understanding the infrastructure of the brain in health and disease

An exploration into understanding the machinery that supports brain health during development and as we mature

Top view 3D depiction of the growth cone C domain where molecular components of the growth cone are segmented and colour-coded using a neural network algorithm.

If our brains are like bustling cities, then the billions of neurons that make up the brain, serve as the city's inhabitants. These neurons connect and communicate, enabling us to think, remember, and understand the world around us. But just like any city needs strong infrastructure to function properly, our neurons rely on a complex system called the cytoskeleton to stay healthy and active. Understanding how this neuronal infrastructure works is crucial. Professor Carolyn Moores and her research team have been exploring the infrastructure of neurons for exactly this reason. Read the below Q&A to find out more.   

What happens if neuron connectivity and operation breaks down? 

Healthy brain function throughout our lives depends on the connections between our neurons being well maintained, and severe human diseases can occur if neuron connectivity and operation breaks down at any stage. Inaccurate neuron movement during brain development can cause intellectual disability, epilepsy and early death. Incomplete maintenance of neuronal function as our brains mature into adulthood can also cause neuropsychiatric illnesses including schizophrenia. Breakdown of neuronal function as we age can cause neurodegenerative disorders. In all these disease scenarios, there remains much to learn, and work in my lab is seeking to understand the machinery that supports neuronal health during development and as we mature. 

What part of neuronal machinery is your research exploring and why is it important?  

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 neuron movement during development, along with maintenance of connectivity and communication in mature neurons. Breakdown or disruption of the neuronal cytoskeleton is associated with developmental syndromes, neurodegenerative diseases and neuropsychiatric illnesses. Studying the cytoskeleton machinery is important so we can understand both how healthy neurons operate and how machinery malfunction causes disease.  

What element of cytoskeleton machinery are you focusing on?  

This project will concentrate on a part of the cytoskeleton called microtubules, understanding further how they are assembled and maintained to help neurons undertake their many complex tasks within the brain Microtubules 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 organisation and stability of the microtubule machinery, together with the particular type of cargo that is carried along it, defines how the neuron functions.  

What’s your research methodology 

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 that have either been assembled in a test tube or are formed within a living neuron. We then use computers to combine these electron microscope pictures to calculate the microtubules’ three-dimensional shape.  

What has your research found (so far)?  

We have been investigating one key protein component of the neuronal cytoskeleton, doublecortin, which when disrupted causes severe neurodevelopmental disease. Our recent work has shown that doublecortin may play a role in repair of damaged neuronal microtubules. We have also been able to pinpoint positions within doublecortin that are mutated in patients to help further understand its role in neurodevelopmental disease. 

What impact has your research had in the wider world?  

The methods we have developed to understand neuronal microtubule structure have been used by groups around the world trying to understand microtubule function and misfunction in a variety of contexts, including in drug development. In the future, knowledge arising from our work may allow us to target and repair the broken parts of the cytoskeleton machinery in diseased or damaged neurons. Such understanding could also shed light on new treatments for dementia, stroke and physical injury. 

“Breakdown of neuronal function as we age can cause neurodegenerative disorders. In all these disease scenarios, there remains much to learn, and work in my lab is seeking to understand the machinery that supports neuronal health during development and as we mature. ”

Top view 3D depiction of a growth cone C domain with segmented and color-coded molecular components: microtubules (pink), mitochondria (yellow), ribosomes (red), other membrane organelles (cyan and lilac), and actin filaments (grey).

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