Role of microtubule acetylation in Parkinson's disease

神经细胞（神经元）在大脑中传递信号。它们有一个细胞体和长长的线状延伸物（可达数十英寸），连接到其他神经元。这些延伸被称为轴突。在帕金森氏症中，产生一种叫做多巴胺的化学物质的神经元的轴突被破坏，连接丢失。这会导致神经元死亡，因此大脑中的多巴胺减少。大脑中多巴胺的缺乏会导致与帕金森病相关的典型震颤、行走和说话问题。这个项目的研究是为了找出帕金森病中神经元是如何死亡的。我们特别关注一个叫做“轴突运输”的过程。轴突运输就像皇家邮政的包裹力，但在神经元中;它将各种货物运送到轴突中的目的地。从技术上讲，轴突运输就像火车旅行：分子发动机（“火车头”）连接到货物（“车厢”）上，它们行驶在称为微管（“铁轨”）的蛋白质轨道上，并使用称为ATP的“燃料”。当轴突运输中断时，轴突会因为没有传递而挨饿，最终神经元死亡。一种名为LRRK 2的基因突变是家族性帕金森病最常见的原因（约7/100），也见于散发性更常见的疾病形式（约3/100）。我们发现突变的LRRK 2阻止了一种叫做线粒体的货物的轴突运输（线粒体在细胞中产生能量，并且已知与帕金森病有关）。我们的研究表明，突变LRRK 2最有可能通过破坏微管轨道来停止轴突运输。利用这些信息，我们测试了一些作用于微管的药物，并发现了一种能够修复有缺陷的轴突运输的药物。这种药物被称为TSA（阿伐他汀-A的缩写）。为了测试这一发现是否适用于整个生物体，我们转向了果蝇（拉丁语为Drosophila）的帕金森病模型。这些果蝇具有导致人类疾病的LRRK 2突变，并且难以攀爬和飞行。因此，这些果蝇以自己的方式有类似于人类帕金森氏症患者的运动困难。我们给这些果蝇喂食TSA，我们发现TSA不仅挽救了轴突运输缺陷，而且还改善了果蝇的运动问题。所以，至少在果蝇中，一种改变微管的药物起作用了。然而，苍蝇不是人类，为了使这种可能的疗法进入临床，还需要更多的工作。在这个项目中，我们想研究TSA如何恢复运输，以及为什么它能保护神经元免于死亡。最有可能的解释是TSA通过增加微管的乙酰化修饰来起作用。我们的第一个目标是调查是否如此。其次，我们不知道这种药物是否作用于特定的LRRK 2相关通路，或者它是否作用于一个不相关但仍然有益的水平。你可以将其与止痛药（如扑热息痛）进行比较，扑热息痛可以缓解疼痛，但不能治愈疼痛的原因。我们认为LRRK 2可能作用于调节微管乙酰化的蛋白质。这就是我们在第二个目标中要研究的。最后，我们想知道这种新的机制是否也涉及其他形式的帕金森病，而不是由突变LRRK 2引起的。这对于建立靶向微管的药物作为治疗所有帕金森病的可能益处是重要的。总之，通过这个项目，我们希望在理解帕金森病中神经元死亡的原因方面取得重大进展。我们已经发现了一种可能有益的药物，现在我们想知道这种药物是如何做到这一点的。这对于设计最佳治疗策略和避免再次失败的临床试验的失望是必要的。如果我们成功了，我们将更接近开发TSA等药物作为帕金森病的治疗方法。

Nerve cells (neurones) transmit signals in the brain. They have a cell body and long string-like extensions (up to tens of inches) that connect to other neurones. These extensions are called axons. In Parkinson's disease the axons of neurones that produce a chemical called dopamine break down and connections are lost. This causes the neurones to die and as a result there is less dopamine in the brain. This shortage of dopamine in the brain causes the typical tremor, walking and talking problems associated with Parkinson's disease. The research in this project is to find out how neurones die in Parkinson's disease. We concentrate particularly on a process called "axonal transport". Axonal transport is like the Royal Mail's Parcel-Force but in neurones; it delivers all kinds of goods to their destinations in the axon. Technically axonal transport is like a train journey: Molecular motors ("the locomotives") hook up to cargoes ("the carriages"), and they ride on protein tracks called microtubules ("the rails") and use a "fuel" called ATP. When axonal transport breaks down the axon starves because no deliveries are being made, and eventually the neurone dies. Mutations in a gene called LRRK2 are the most common cause of familial Parkinson's disease (~7 in 100) and are also found in the sporadic, more common form of the disease (~3 in 100). We have found that mutant LRRK2 stops axonal transport of a cargo called mitochondria (which produce energy in the cell and are known to be involved in Parkinson's disease). Our investigations revealed that mutant LRRK2 most likely stops axonal transport by damaging the microtubule rails. Using this information we tested a number of drugs that act on microtubules and found one that was able to repair the defective axonal transport. This drug is called TSA (short for trichostatin-A). To test if this finding held up in a whole living organism we turned to a model of Parkinson's disease in fruit flies (Drosophila in Latin). These flies have the human disease causing LRRK2 mutations and have difficulties climbing and flying. So in their own way these flies have movement difficulties similar to those of human Parkinson's patients. We fed these flies TSA and we found that not only did TSA rescue the axonal transport defect but it also improved the movement problems of the flies. So, at least in the fruit fly a drug that modifies microtubules is working. However, flies are not humans and for this possible therapy to make it to the clinic more work is needed.In this project we want to investigate how TSA restores transport and why it protects neurones from dying. The most likely explanation is that TSA works by increasing a modification of microtubules called acetylation. Our first aim is to investigate if this is so. Secondly we don't know if the drug works on a specific LRRK2 related pathway or if it acts on an unrelated, but still beneficial, level. You can compare this with a painkiller such as paracetamol that relieves pain but doesn't cure the cause of the pain. We think that LRRK2 may act on proteins that regulate the acetylation of microtubules. This is what we want to investigate in our second aim. Finally, we want to find out if this novel mechanism is also involved in other forms of Parkinson's disease that are not caused by mutant LRRK2. This is important to establish the possible benefits of drugs that target microtubules as a therapy for all Parkinson's disease.In summary with this project we want to make significant inroads into understanding the reasons why neurones die in Parkinson's disease. We have already found a drug that may be beneficial and we now want to find out exactly how the drug does this. This is necessary to design the best therapeutic strategies and to try to avoid the disappointment of yet another failed clinical trial. If we are successful we will be one step closer to develop drugs such as TSA as a therapy for Parkinson's disease.