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

帕金森氏症(PD)是一种常见的大脑疾病，在英国有12.7万人受到影响。它会导致运动缓慢和其他症状，如便秘和记忆力丧失。与癌症医学不同，帕金森病的根治疗法进展甚微。在癌症医学中，患者的治疗不仅取决于癌症发生的部位(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方法。事实证明，这种“个人化医疗”的想法非常成功。目前，所有帕金森病患者都接受了相同类型的治疗，以帮助缓解病情的症状，但没有治疗方法来阻止或治愈帕金森病。许多治疗方法在老鼠身上试验时显示出有希望的结果，但当在人类身上试验时，它们没有显示出任何好处。这些令人失望的结果的一个关键原因可能是，与癌症药物不同，所有帕金森氏症患者都得到了相同的治疗。帕金森病在有条件的人中差异很大，例如，一些人的症状会在短期内恶化，而一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不清楚，但一种可能性是，尽管所有帕金森氏症患者大脑的同一部分都受到影响，但该特定区域如何受到影响可能因人而异。长期以来，线粒体(神经细胞的“动力站”)受损一直被认为是帕金森病的一个重要特征。然而，现在越来越多的人达成共识，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，那么它应该在线粒体损伤更重要的人身上进行试验。不幸的是，目前还没有通过症状、脑扫描或血液测试来检测帕金森氏症患者是否有严重的线粒体损伤的方法。由于之前针对线粒体的药物试验是在一组未选定的帕金森氏症患者中进行的，其中许多人不会有明显的线粒体损伤，因此降低了药物显示任何益处的机会。对于帕金森氏症未来的药物试验，我认为重要的是我们确定哪些人最有可能从药物中受益，并针对这些人进行适当的试验。使用一种新的方法，我希望尝试并确定一种可靠的检测方法，从血液样本中检测哪些帕金森氏症患者有线粒体损伤。这样的血液测试将彻底改变线粒体疗法的药物试验，因为它不仅可以让“正确的”药物针对“正确的”人(就像在癌症医学中那样)，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.