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

用遗传学方法研究正常衰老过程中半胱氨酸串蛋白的神经保护作用

• 批准号: BB/J005843/1
• 负责人: Robert Burgoyne
• 金额: $ 46.11万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ005843%2F1
• 关键词: genetic; approach; study; neuroprotective; role

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.

神经功能的减少和神经元的丧失发生在正常的衰老过程中，并在神经退行性疾病中加速。在了解突变基因如何导致疾病中神经退行性变加速方面已经付出了很多努力，但在了解正常衰老过程中神经元保护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特定的蛋白质，这些蛋白质参与保护神经元免受由于其高水平的持续活动而可能发生的损伤。神经元之间交流的一个关键方面是由于神经元之间的连接处（突触）释放的小神经递质。突触内的蛋白质对神经递质的释放至关重要；这些都是多次使用，必须非常迅速地回收使用。蛋白质的功能通常受到所谓的伴侣蛋白的保护。其中一种伴侣是半胱氨酸弦蛋白（CSP），它存在于突触中，并与负责神经递质释放的蛋白质相互作用。在对其基因被破坏的小鼠的研究中，发现了CSP在神经保护中的关键生理作用。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。当相同的基因被破坏时，在这些老鼠和苍蝇身上都可以看到神经变性的证据。我们最近研究了存在于秀丽隐杆线虫中的CSP。秀丽隐杆线虫由于其相对简单，易于遗传操作和简单功能分析的可用性而被广泛用作模式生物。重要的是，许多生物过程的基本机制，如衰老，在从蠕虫到人类的生物体中都是保守的，并且涉及所有物种的等效蛋白质。我们最近的研究表明，缺乏功能性CSP的蠕虫在衰老过程中会出现运动缺陷、寿命缩短和神经元的逐渐丧失。这表明CSP参与了防止神经元退化和死亡所需的进化保守的基本机制。我们将使用蠕虫遗传方法的力量来解剖CSP作用的途径，并确定在其缺失时发生的神经退行性变的新调节因子。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。

项目成果

Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol.

• DOI: 10.1093/hmg/ddu316
• 发表时间: 2014-11-15
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Kashyap SS;Johnson JR;McCue HV;Chen X;Edmonds MJ;Ayala M;Graham ME;Jenn RC;Barclay JW;Burgoyne RD;Morgan A
• 通讯作者: Morgan A

Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression.

• DOI: 10.1186/s13024-015-0046-3
• 发表时间: 2015-09-29
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Chen X;McCue HV;Wong SQ;Kashyap SS;Kraemer BC;Barclay JW;Burgoyne RD;Morgan A
• 通讯作者: Morgan A