Molecular and functional characterisation of the neuronal specific de-ubiquitinase UCH-L1 and its role in neuronal polarity and axonal outgrowth

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Nerves cell communicate by passing information across synapses. Synapses are structures formed between axons, which relay information out of the nerve cell, and dendrites, which receive information into the cell. In general, synapse formation requires the growth and elongation of axons to find dendrites of other cells. This process sounds simple but, in fact, it requires a highly regulated and coordinated series of events. One of the first things that need to happen is that the cell has to specify which protrusion will be an axon and which will be dendrites. This process is known as polarization and usually results in a single long axon and much smaller dendrites.The molecular events that regulate neuronal polarization and subsequent axonal outgrowth are not well understood. However, it is clear that the targeted destruction of proteins is an important factor. For example, the main function of some proteins is to block the effects of other proteins. It is only when the first protein is destroyed that the second protein can exert its effects. A major way cells destroy proteins is by tagging them with a small marker protein called ubiquitin. The ubiquitin tag acts as an identifier that allows these proteins to be recruited to the proteasome, a structure that breaks down and recycles unwanted proteins. We have recently discovered that UCH-L1, a protein that is only present in neurons, plays a key role in regulating the ubiquitin tagging of proteins and that one of its actions is to enhance axonal growth. Our aim is to understand how UCH-L1 does this, what other proteins are involved and what happens when it goes wrong. We believe that this is important because it will provide information about how nerve cells connect and how they form networks, which are the basis of how the brain works. In addition, UCH-L1 is associated with a number of important diseases, such as Parkinson's and Alzheimer's diseases, so better understanding of UCH-L1 function could provide a ways to design drugs to help treat these conditions.