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）构成，而且由神经胶质细胞构成。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适当平衡。这些功能对于维持我们一生中健康的神经系统至关重要，并且在许多神经系统退行性疾病和正常衰老中经常被破坏。大多数关于神经胶质细胞功能的研究都是在像老鼠这样的实验动物身上进行的。替代或减少动物实验的策略通常涉及在培养皿中培养和操作细胞。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，这些替代策略就不那么简单了，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神经胶质）放在一起并加以操作。我们建议用一种小型无脊椎生物——果蝇来代替老鼠。这种实验室生物的神经系统中有神经胶质细胞，这种神经胶质细胞执行人类的所有功能。果蝇还含有相当于所有已知与人类疾病有关的基因的约70%，它经济且易于维护和操作，并已在许多实验室广泛使用了一个多世纪。我们之前的工作已经在果蝇中产生了一种罕见的人类神经退行性疾病的遗传模型。这表明了神经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，功能失调的神经胶质细胞不能正常地与神经元相互作用，这损害了神经系统的功能，缩短了寿命。我们建议用我们的果蝇模型作为一种工具来发现神经胶质细胞的作用，并确定那些参与神经胶质和神经元之间交流的基因，这些基因对健康的神经系统至关重要。虽然具体的病理将被用作一个方便的起点，但我们已经设计了我们的项目，以便它可以发现保证神经系统正常功能的机制。这些发现也可能被认为是未来药理学研究的目标，这些研究将利用胶质-神经元通讯来改善神经退行性疾病患者的健康。如果我们成功了，我们就不需要在我们的实验室里用老鼠来研究这个问题，这也会鼓励我们的实验室和其他对这些问题感兴趣的实验室减少使用老鼠。测试我们在苍蝇身上的发现是否也适用于老鼠，比从头开始在老鼠身上进行新的研究更有趣，也更直接。在第一种情况下，较少的动物将需要用于实验，因为这些实验将不受假设的指导，而是来自于对同样的事情如何在果蝇中起作用的精确知识，因此可以更好地计划。总之，我们的工作对于思考改善神经退行性疾病患者健康的新方法以及减少动物实验都可能非常重要。

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.