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Research unravels nerve-wiring process

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2 August 2012

Research published in The Journal of Neuroscience has unravelled key mechanisms that underpin the development of our nervous system. The BBSRC-funded researchers from The University of Manchester have provided detailed understanding of the machinery involved in wiring up the connections that allow for signals to travel between our brain and target cells. The findings also open up new avenues in the investigation of neurodegenerative diseases and the gradual decay of brain capacity during ageing by analysing the cellular processes underlying these conditions.

Our nervous system is like a highway for information where thin cable-like extensions called 'axons' wire the brain to other cells. In order to build these connections, nerve cells extend long, slender projection throughout our body from one point to another. The importance of these information highways is best illustrated when they are lost, for example through sustained paralysis upon spinal injury or permanent loss of coordination after stroke.

Dr Prokop and his team used fruit flies to analyse the process of axon growth.
Dr Prokop and his team used fruit flies to analyse the process of axon growth.

The growth of these axons is directed by a hand-shaped growth cone which sits at the tip of the axon. It is well documented how growth cones perceive signals from the outside to follow pathways to specific targets, but very little is known about the internal machinery that dictates their behaviour.

Dr Andreas Prokop explains: "The axon extends to build connections that link point-to-point over relatively long distances. If you think of it as laying roads for a highway, we have a good understanding of how the direction is established but we know very little about the tools used to lay the tarmac."

Dr Prokop has been studying the key driver of growth cone movements, the cytoskeleton. The cytoskeleton helps to maintain a cell's shape and is made up of the protein filaments, actin and microtubules. Microtubules are the key driving force of axon growth whilst actin helps to regulate the direction the axon grows.

Dr Prokop added: "We've been looking closely at the cytoskeleton, because it is the machinery needed to produce and maintain axons. But the cytoskeleton is difficult to study in nerve cells due to its complexity."

The scientists have overcome the complexity issue by understanding the process in the simple model organism, the tiny fruit fly Drosophila. Dr Prokop and his team used these fruit flies to analyse how actin and microtubule proteins combine in the cytoskeleton to coordinate axon growth. They focussed on the multifunctional proteins called spectraplakins which are essential for axonal growth and have known roles in neurodegeneration and wound healing of the skin.

What the team demonstrate in this recent paper is that spectraplakins link microtubules to actin to help them extend in the direction the axon is growing. If this link is missing then microtubule networks show disorganised criss-crossed arrangements instead of parallel bundles and axon growth is hampered.

By understanding the molecular detail of these interactions the team made a second important finding. Spectraplakins collect not only at the tip of microtubules but also along the shaft, which helps to stabilise them and ensure they act as a stable structure within the axon.

This additional function of spectraplakins relates them to a class of microtubule-binding proteins including Tau. Tau is an important player in neurodegenerative diseases, such as Alzheimer's, which is still little understood. In support of the author's findings, another publication has just shown that the human spectraplakin, Dystonin, causes neurodegeneration when affected in its linkage to microtubules.

Talking about his research Dr Prokop said: "Understanding cytoskeletal machinery at the cell level is a holy grail of current cell research that will have powerful clinical applications. Thus, cytoskeleton is crucially involved in virtually all aspects of a cell's life, including cell shape changes, cell division, cell movement, contacts and signalling between cells, and dynamic transport events within cells. Accordingly, the cytoskeleton lies at the root of many brain disorders. Therefore, deciphering the principles of cytoskeletal machinery during the fundamental process of axon growth will essentially help research into the causes of a broad spectrum of diseases. Spectraplakins lie at the heart of this machinery and our research opens up new avenues for its investigation"

What Dr Prokop also demonstrates is the successful research technique using the fruit fly Drosophila. In a previous publication, the team had already shown that roles of spectraplakins during axon growth apply likewise in mice which in turn mean the findings can be translated to humans.

Dr Prokop points out fruit flies provide ideal means to make sense of these findings and essentially help to unravel the many mysteries of neurodegeneration.

Dr Prokop continues: "Understanding how spectraplakins perform their cellular functions has important implications for basic as well as biomedical research. Thus, besides their roles during axon growth, spectraplakins of mice and humans are clinically important for a number of conditions and processes including skin blistering, neuro-degeneration, wound healing, synapse formation and neuron migration during brain development. Understanding spectraplakins in one biological process will instruct research on the other clinically relevant roles of these proteins."

The recently published paper represents six years of work by Dr Prokop and his dedicated team.


Notes to editors

The paper is entitled "Spectraplakins Promote Microtubule-Mediated Axonal Growth by Functioning As Structural Microtubule - Associated Proteins and EB1-Dependent +TIPs (Tip Interacting Proteins)."

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