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

神经元功能的降低和神经元的损失发生在正常衰老期间，并且在神经退行性疾病中加速。人们已经投入了大量的精力来了解突变的基因如何导致疾病中神经退行性变的加速，但在了解正常衰老过程中保护神经元的基本机制方面所做的工作要少得多。越来越多的证据已经开始确定参与保护神经元免受由于其高水平持续活动而可能发生的损伤的特定蛋白质。神经元之间的通信的一个关键方面是由于神经元之间的接点（突触）处的小神经递质的释放。突触内的蛋白质对于神经递质的释放至关重要;这些神经递质被多次使用，并且必须非常迅速地回收利用。蛋白质的功能通常由所谓的伴侣蛋白保护。一种这样的分子伴侣是半胱氨酸串蛋白（CSP），其在突触中发现并与负责神经递质释放的蛋白质相互作用。CSP在神经保护中的关键生理作用出现在其基因被破坏的小鼠的研究中。这些小鼠出生时正常，但表现出进行性异常，并在几周后死亡。在这些小鼠中发现了神经变性的证据，当同等基因被破坏时，也在苍蝇中发现了神经变性的证据。我们最近研究了CSP存在于线虫秀丽隐杆线虫。C.秀丽线虫由于其相对简单、易于遗传操作和简单功能测定的可用性而被广泛用作模式生物。重要的是，许多生物过程（如衰老）的基本机制在从蠕虫到人类的生物体中是保守的，并涉及所有物种中的等效蛋白质。我们最近的工作表明，缺乏功能性CSP的蠕虫在运动中表现出年龄依赖性缺陷，寿命缩短，并且在衰老过程中神经元逐渐丧失。这表明CSP参与了防止神经元变性和死亡所需的进化保守的基本机制。我们将利用蠕虫遗传学方法的力量来剖析CSP作用的途径，并确定在其缺失情况下发生的神经变性的新调节因子。这些研究将深入了解正常衰老过程中神经保护的生理重要性途径。

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.