A genetic approach to the study of the neuroprotective role of cysteine string protein during normal ageing

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A reduction in neuronal function and loss of neurons occurs during normal ageing and is accelerated in neurodegenerative diseases. Much effort has been put into understanding how mutated genes can lead to acceleration of neurodegeneration in disease but much less work has been done on understanding the basic mechanisms for the protection of neurons during normal ageing processes. Increasing evidence has begun to identify specific proteins that are involved in the protection of neurons from damage that can occur due to their high level of ongoing activity. A key aspect of communication between neurons is due to the release of small neurotransmitters at the junctions (synapses) between neurons. Proteins within the synapses are crucial for the release of neurotransmitters; these are used multiple times and have to be recycled for use very rapidly. The functions of proteins are often protected by so called chaperone proteins. One such chaperone is cysteine string protein (CSP) that is found in synapses and interacts with the proteins responsible for neurotransmitter release. A key physiological role for CSP in neuroprotection emerged in study of mice in which its gene had been disrupted. These mice were born normal but showed progressive abnormalities and died after a few weeks. Evidence for neurodegeneration was seen in these mice and also in flies when the equivalent gene was disrupted. We have recently studied the CSP present in the nematode worm Caenorhabditis elegans. C. elegans has been widely used as a model organism due to its relative simplicity, the ease of genetic manipulation and the availability of simple functional assays. Importantly, many of the basic mechanisms underlying biological processes such as ageing are conserved in organisms from worms to man and involve the equivalent proteins in all species. Our recent work has shown that worms lacking functional CSP show age-dependent defects in movement, reduced life-span and a progressive loss of neurons during ageing. This suggests that CSP is involved in an evolutionarily conserved basic mechanism required to prevent the degeneration and death of neurons. We will use the power of worm genetic approaches to dissect the pathways by which CSP acts and to identify new regulators of the neurodegeneration that occurs in its absence. These studies will give insight into pathways of physiological importance in neuroprotection during normal ageing.