An integrated biochemical, genetic and transcriptomic approach to defining target therapeutic pathways in Parkinson's disease

帕金森氏症（PD）是一种常见的脑部疾病，在英国影响着12.7万人。它会导致行动迟缓和其他症状，如便秘和记忆力减退。与癌症医学不同，帕金森病的治愈治疗几乎没有进展。在癌症医学中，对患者的治疗不仅取决于癌症的发展部位（如乳腺癌、肠癌或前列腺癌），还取决于癌细胞所含的特定蛋白质，因此两名乳腺癌患者可能会接受两种截然不同的治疗。事实证明，这种“个性化医疗”的理念非常成功。目前，所有PD患者都接受相同类型的治疗，以帮助缓解症状，但没有治疗方法可以停止或治愈PD。许多治疗方法在老鼠身上试验时显示出有希望的结果，但在人类身上试验时却没有显示出任何益处。这些令人失望的结果的一个关键原因可能是，与癌症医学不同，所有PD患者的治疗都是一样的。PD患者之间的差异相当大，例如，有些人的症状会在短时间内恶化，有些人的症状在多年后几乎没有变化。这种差异的原因在很大程度上仍然未知，但一种可能性是，尽管所有PD患者大脑的同一部分都受到影响，但特定区域受到影响的方式可能因人而异。线粒体（神经细胞的“发电站”）损伤一直被认为是帕金森病的一个重要特征。然而，现在越来越多的人认为，一些帕金森病患者的线粒体损伤可能比其他人更严重。因此，如果一种药物的目标是改善线粒体的功能，那么它应该在那些线粒体损伤更严重的人身上进行试验。不幸的是，目前还没有办法通过症状、脑部扫描或血液检查来检测帕金森病患者是否有明显的线粒体损伤。由于先前针对线粒体的药物试验是在一组未经选择的帕金森病患者中进行的，其中许多人没有明显的线粒体损伤，因此减少了药物显示任何益处的机会。我认为，对于帕金森症药物的未来试验，重要的是我们要确定那些最有可能从药物中受益的人，并针对这些人进行适当的试验。使用一种新颖的方法，我希望尝试并确定一种可靠的测试，可以从血液样本中检测出哪些PD患者有线粒体损伤。这种血液测试将彻底改变线粒体治疗的药物试验，因为它不仅可以将“正确”的药物指导给“正确”的人（就像癌症药物一样），而且还可以作为判断药物是否有效的测试。

Parkinson's disease (PD) is a common brain disorder affecting 127,000 people in the UK. It causes slowness of movement and other symptoms such as constipation and memory loss. Unlike cancer medicine, there have been few advances in curative treatment for PD. In cancer medicine patients' treatment is directed not only by where the cancer has developed (e.g. breast, bowel or prostate) but also by the particular proteins that the cancer cells have, so that two people with breast cancer may be treated with two very different treatments. This idea of 'personalised medicine' has proven very successful. Currently all people with PD are given the same type of treatment to help with the symptoms of the condition but no treatments exists to stop or cure PD. Many treatments have shown promising results when tested in mice but when trialled in humans they failed to show any benefit.A key reason for these disappointing results may be that, unlike in cancer medicine, all people with PD are treated the same. PD varies quite considerably within those with condition, for example some have symptoms that worsen over a short period and some have very little change in their symptoms over many years. The reason for this variation is still largely unknown, but one possibility is that although the same part of the brain is affected in all people with PD, how that particular area becomes affected may differ from person to person. Damage to mitochondria (the "power stations" of nerve cells) has long been implicated as an important feature of PD. However, there is now growing consensus that mitochondrial impairment may be greater in some people with PD than others. Therefore if a medicine targets improving the function of mitochondria then it should be trialled on those people where mitochondrial impairment is more important. Unfortunately there is no current way of detecting by symptoms, brain scans or blood tests if a person with PD has significant mitochondrial impairment. As such previous trials of medications targeted at mitochondria have been carried out in an unselected group of people with PD, many of which would not have significant mitochondrial impairment, therefore reducing the chance that the medication would show any benefit.For future trials of medicines in Parkinson's I believe it is important we identify those who would most likely benefit from the medication and target those people to the appropriate trial. Using a novel approach I wish to try and identify a reliable test that detects which people with PD have mitochondrial impairment from a blood sample. Such a blood test would revolutionise drug trials for mitochondrial therapy as not only would it allow the 'right' medication to be directed to the 'right' person (as it is in cancer medicine) but may also act as test to judge if the medication is effective.