At the British Neuroscience Association (BNA)’s Festival of Neuroscience in April 2019, we were lucky enough to sit down with some influential neuroscientists to discuss their work. We’ve assembled these transcripts into our BNA Interview Series. Here we interview University College London’s John Hardy, whose work into the genetics of neurodegenerative disorders saw him share the大脑奖在2018年。

Ruairi Mackenzie（RM）：例如，遗传学对例如阿尔茨海默氏病等神经退行性状况有多大影响？

约翰·哈迪（JH）：I think it started slowly in the 80’s and 90’s, as we, and I mean we generally, started to find genes for disease but I think gradually it’s become the dominant force for how people in general start to get at the pathogenesis of all neurodegenerative diseases. So I think there was a bit of a slow uptake of people understanding the significance of genetics, but now it’s become the dominant way people understand pathogenesis, I think.

RM：疾病的遗传形式与其他形式有什么区别？

JH：There is no clear answer to that, but to deal with Alzheimer’s disease first, in the early onset autosomal dominant forms of the disease, where you have mutations in either the amyloid gene which we found, or the presenilin genes which Peter Hyslop found, those people over produce amyloid. In the sporadic forms of the disease, the late onset forms of the disease, the predominant problem is a failure to degrade and remove amyloid from the brain. So, there is a distinction but they’re consistent with each other.

RM：这些遗传研究人员如何为寻找治疗和疗法做出贡献？

JH：好吧，我们还没有治疗和疗法，说实话。因此，我们还没有进球，因此谈论谁是最好的进球者，这真的还为时过早。我认为，当然，遗传发现驱动了我们寻找治疗方法的方式，但是说实话，我们还没有得到这些治疗，因此我们必须对此有些谦虚。

RM: What role do you think going forward these genetic studies will have advances our understanding of these diseases in getting that goal, eventually?

JH：Well I hope that they will have profound, successful implications. What we have found recently, and again I use the word ‘we’ in a general sense and not to mean my own group, but we have found genes involved in the microglial response to amyloid induced damage and I think that’s a significant understanding which should help us think about how we might fine tune the response to amyloid induced damage.

RM：我了解一些遗传研究 - 您提到的小胶质细胞 - 已将免疫系统牵涉到阿尔茨海默氏症中。您能谈谈这些关系是如何相关的吗？

JH：通过免疫系统，就大脑而言，我们的意思是小胶质细胞。这就是我们的意思，因此，当我们说明显参与阿尔茨海默氏病的免疫系统时，我们在很大程度上，也许不是只有，但我们在很大程度上意味着小胶质细胞如何反应？小胶质细胞对淀粉样蛋白沉积的反应如何？我们发现的基因之一称为TREM2。这是一个小胶质细胞基因，它参与了损害膜的淀粉样蛋白沉积物的小胶质细胞的趋化性。我要提到的另一个基因是一个称为AVCA7的基因，即磷脂清除和磷脂是膜的主要成分。因此，这两个基因都被视为淀粉样膜损伤反应基因。

RM: We’ve mentioned Alzheimer’s but in the same way that there is a lot of common mechanisms in neurodegenerative diseases. Are microglial responsible for clearing up TSP-43 or other pathological proteins?

JH：实际上，TDP-43是我最了解的TDP-43，因此我们可以滑过它。我只想说TDP-43参与了所有细胞的损伤响应，但是可以说特别是运动神经元及其所涉及的是，当神经元受损时，会隔离信使RNA。因此，这是一种损伤响应蛋白本身，看起来TDP-43中的突变是弄乱了损害响应。当神经元损坏时，它们会隔离RNA并切换转换为热激蛋白，例如，TDP-43参与收集当前正在翻译的使者，然后当损坏通过时，它们会释放那些使者以及突变的突变。似乎这样做是阻碍了后来的使者。因此，这再次是损伤反应蛋白。

RM：我们是否看到更多地看到这些疾病是对淀粉样蛋白等蛋白质反应的问题，因此将我们的疗法转移到靶向这种反应的问题上？

JH：是的，部分肯定。我认为我们也应该想的要比我们所做的更多，这导致了病理反应的最初损害是什么，也许我们对所有疾病类别都没有对此进行过足够的思考。

RM：您认为这是不可避免的衰老的一部分吗？

JH：You know, inevitable is a strong word. I think one thing that science can take credit for, though not neurodegeneration researchers, is the fact that the incidence of dementia has dropped about 25% over the last 30 years. We haven’t understood why that is precisely but one of the leading ideas about that is that it coincides with better heart health, through blood pressure control, for example. One might suppose that inadvertently we have made progress but it’s sadly not through research into neurodegenerative disease, but through the good efforts of our heart disease colleagues basically. So I don’t think inevitable. Inevitable is too strong a word but also, I don’t think we neurodegeneration researchers can take the credit for it.

RM：我明白了。您是否认为我们最终将拥有某种生活方式，甚至是人们可以作为预防性服用的药物，这首先会阻止损害发生？

JH：是的for sure, I think one thing I do think is that – and I think the field is in agreement with this – there is going to be no magic bullet for Alzheimer’s disease. I think it’s going to be a mixture of maybe drugs and lifestyle suggestions. I will just mention, because I think it is the most exciting thing of the last two years, that the treatment of spinal muscular atrophy through antisense treatment is really perhaps something we should be looking across the board for, in terms of treatments and I have been very excited by the anti-Huntington therapies based on the antisense therapies. If they work, one can see a way of using the same approaches across the board in neurodegenerative diseases. So I do think there is hope, I’m very excited about those things, but I don’t think there is going to be a magic bullet.

RM：如果没有魔术弹药，您是否认为制药公司将是该领域有兴趣的合作伙伴，还是我们需要让机构和公共资助者领导？

JH：这将是两者的混合。我很震惊地看到辉瑞两年前退出了神经退行性研究。我认为这是一个错误，但是现在我们对这些疾病的了解要比四到五年前更多，而遗传学一直是其中的很大一部分。我们了解我认为的疾病机制比我们要好得多，因此我认为肯定有希望，但是它将融合大型制药，生物技术和学术资金，这三个主要领域需要加入。他们需要以建设性的方式互相交谈。我对UCL感到兴奋的一件事是，阿尔茨海默氏症研究所英国的资金试图弥合这三个研究领域之间的差距，以尝试使一条更加无缝的管道。比利时罗马尼亚比分直播

约翰·哈迪（John Hardy）正在与技术网络科学作家Ruairi J Mackenzie交谈捷克葡萄牙直播