Drosophila as a model to understand the role of glial cells in neurodegeneration

人类和所有复杂生物体的神经系统不仅由神经细胞(神经元)组成，也由神经胶质细胞组成。胶质细胞具有许多重要的功能，如绝缘、营养支持和维持信号物质的正确平衡。这些功能对我们一生中保持健康的神经系统至关重要，在许多神经系统退行性疾病中经常被破坏，在正常年龄也是如此。大多数关于胶质细胞功能的研究都是在小鼠等实验室动物身上进行的。替代或减少动物实验的策略通常涉及培养和操纵培养皿中的细胞。然而，由于神经胶质细胞的功能与其对神经元的影响密切相关，这些替代策略不那么直接，因为有必要将两种或两种以上的细胞类型(神经元和不同种类的胶质细胞)组合在一起并进行操作。我们建议用一种小型无脊椎动物--果蝇来取代小鼠。这种实验室生物的神经系统中有胶质细胞，这种胶质细胞执行人类的所有功能。果蝇还含有约70%的已知与人类疾病有关的基因，它经济、易于维护和操作，一个多世纪以来已在许多实验室广泛使用。我们之前的工作建立了果蝇一种罕见的人类神经退行性疾病的遗传模型。这表明了胶质细胞的严重缺陷，这缩短了苍蝇的寿命，损害了它的运动。一个合理的假设是，功能障碍的神经胶质细胞不能与神经元正确地相互作用，这损害了神经系统的功能，并缩短了寿命。我们建议利用我们的苍蝇模型作为发现胶质细胞的工具，并识别那些参与神经胶质细胞和神经元之间沟通的基因，这些基因对健康的神经系统至关重要。在以特定的病理为方便的起点的情况下，我们设计了我们的项目，以便能够发现保证神经系统正常功能的机制。这些发现也可以被认为是未来药理学研究的目标，这些研究将利用胶质细胞与神经元的沟通来改善神经退行性疾病患者的健康。如果我们成功了，我们将不需要小鼠在我们的实验室研究这个问题，这也将鼓励减少我们实验室和其他对这些问题感兴趣的实验室中的小鼠的使用。比起在老鼠身上开始一项新的研究，测试我们在苍蝇身上发现的东西在老鼠身上是否也是正确的，将会更有趣和直接。在第一种情况下，实验中需要使用的动物将会更少，因为这些实验将不会受到假设的指导，而是基于同样的事情如何在果蝇身上发挥作用的精确知识，因此可以更好地规划。总之，我们的工作可能对思考改善神经退行性疾病的健康的新方法以及减少动物实验都非常重要。

The nervous system in human and all complex organisms is made not only by nerve cells (neurons) but also by glial cells. Glia performs a number of important functions such as insulation, nutritive support and maintenance of the right balance of signalling substances. These functions are essential to maintain an healthy nervous system throughout our lifetime and are often disrupted in many degenerative diseases of the nervous system and also in normal ageing.Most studies on glial cell functions are conducted in laboratory animals like mice. Strategies for replacing or reducing animal experiments usually involve growing and manipulating cells in a dish. However because the function of glial cells is so intimately connected to its effect on neurons, these replacement strategies are less straightforward because it it is necessary to put together and manipulate two or more cell types (neurons and different kinds of glia).We propose instead to replace mice with a small invertebrate organism, the fruitfly. This laboratory organism has glia in its nervous system and this glia performs all the functions found in humans. The fruitfly also contains an equivalent for about 70% of all genes known to be involved in human disease, it is economic and easy to maintain and manipulate, and has been widely used in many labs for over a century.Our previous work has generated a genetic model for a rare human neurodegenerative condition in the fruitfly. This has shown dramatic deficits in glial cells, which shorten the lifespan of the fly and impair its movements. A sensible hypothesis is that malfunctioning glial cells do not interact properly with neurons and this compromises the function of the nervous system and reduces lifespan.We propose to use our fly models as a tool for discovery to figure out the role of glia, and to identify those genes involved in the communication between glia and neurons that are essential for a healthy nervous system.Whereas the specific pathology will be used as a convenient starting point, we have designed our project so that it can discover the mechanisms that guarantee a proper function of the nervous system in general. These findings may be considered also as targets for future pharmacological research that will exploit glia-neuron communication to improve the health of patients with neurodegenerative diseases.If we are successful we will not need mice to study this issue in our lab and this will also encourage reducing the use of mice both in our lab and in other labs interested in these problems. It will be more interesting and straightforward to test whether what we find in flies is also true in mice, than starting a new investigation from the beginning in mouse. In the first case fewer animals will need to be used in experiments, because those experiments will not guided by suppositions, rather from the precise knowledge of how the same thing works in the fruitfly and therefore can be better planned.In conclusion, our work is likely to be very important both for thinking about new ways to improve health in neurodegenerative conditions, and for reducing experiments on animals.