A neurodevelopmental origin of dystonia

保持对身体运动的控制对我们的健康至关重要。然而，许多神经系统疾病会导致这种控制的丧失，降低生活质量。在这里，我专注于一种流行但知之甚少的疾病：肌张力障碍。肌张力障碍的特征是不随意的肌肉收缩，导致扭曲，扭曲的姿势。仅在英国就有超过9万名患者患有这种疾病。肌张力障碍性运动经常是痛苦的，并且可能开始在早期-在某些情况下，出生后几周。此外，肌张力障碍通常与其他疾病症状相关，包括其他运动障碍，如帕金森综合征、共济失调、运动障碍和肌阵挛;以及非运动相关障碍，如癫痫、自闭症、智力残疾和发育迟缓。不幸的是，治疗肌张力障碍的治疗选择有限。这主要是由于缺乏对这种疾病中不自主运动的基本分子和细胞基础的理解。在这个奖学金申请中，我描述了一系列使用果蝇来揭示这种机制的方法，果蝇是一种具有无与伦比的使用速度和非常强大的工具包的模式生物，可以轻松地操纵基因和神经回路。我介绍了一种新的果蝇模型的肌张力障碍，证明该模型表现出肌张力障碍样的运动和神经回路的活动，影响运动的变化，并显示如何使用该模型可以用来揭示细胞通路，导致肌张力障碍。我建议通过产生一系列新的果蝇肌张力障碍模型来证实我们的研究结果的更广泛的相关性，并利用这些模型来确定新的药物治疗。此外，我还建立了一个独特的国家和国际合作者网络，专门研究肌张力障碍遗传学，神经生理学和疾病的小鼠模型。这个网络将使我能够通过使用我们的结果来指导人类和哺乳动物系统的研究，从而大大增加翻译的影响，以确认哺乳动物肌张力障碍模型中潜在药物治疗的有效性。我的实验策略的实施有望大大提高我们对肌张力障碍运动如何产生的理解，并发现治疗这种衰弱性疾病的新治疗方法。实现这些目标也可能揭示了大量的神经系统疾病，经常与肌张力障碍共病。

Maintaining control over bodily movements is critical for our wellbeing. Many neurological diseases, however, result in a loss of such control, diminishing quality of life. Here, I focus on one such disease that is prevalent yet poorly understood: dystonia. Dystonia is characterised by involuntary muscle contractions that result in twisted, contorted postures. Over 90,000 patients in the UK alone suffer from this disease. Dystonic movements are frequently painful and may begin at an early age - in some cases, just weeks after birth. Furthermore, dystonia is often associated with additional disease symptoms, including other movement disorders such as Parkinsonism, ataxia, dyskinesia, and myoclonus; and non-movement-related disorders such as epilepsy, autism, intellectual disability and developmental delay. Unfortunately, therapeutic options to treat dystonia are limited. This is primarily due to a lack of understanding regarding the fundamental molecular and cellular basis of involuntary movements in this disorder. In this Fellowship application, I describe a series of approaches to uncover such mechanisms using the fruit fly, Drosophila melanogaster - a model organism with unparalleled rapidity of use and a hugely powerful toolkit that readily enables manipulations of both genes and neural circuits. I introduce a novel Drosophila model of dystonia; demonstrate that this model exhibits dystonia-like alterations in movement and the activity of neural circuits that influence movement; and show how this model can be used to uncover cellular pathways that cause dystonia. I propose to confirm the broader relevance of our findings by generating a new array of Drosophila dystonia models, and to utilise these models to identify novel drug treatments. Furthermore, I have built a unique network of national and international collaborators specialising in the study of dystonia genetics, neurophysiology, and mouse models of the disease. This network will allow me to greatly increase translational impact by using our results to guide studies in human and mammalian systems, to confirm the validity of potential drug treatments in mammalian dystonia models. Implementation of my experimental strategy promises to greatly enhance our understanding of how dystonic movement arise, and uncover novel therapeutic methods to treat this debilitating disorder. Achieving these goals may also shed light on the large number of neurological diseases that are frequently co-morbid with dystonia.