Understanding and treating neurogenetic conditions related to the Kennedy pathway

遗传性痉挛性截瘫S是一大组导致肢体无力和僵硬(痉挛)的遗传性疾病。不幸的是，病情发展，导致患者经历越来越多的困难。在某些形式的过敏性紫杉醇过敏症中，症状仅限于腿部，而其他患者可能遭受更广泛的医疗问题(称为复合性过敏性紫杉醇)。在这项提案中，我们将研究两种复杂形式的热休克蛋白，称为SPG81和SPG82。这些复杂的热休克蛋白是由编码所谓的肯尼迪脂代谢途径的酶的基因突变引起的。这种途径产生两种类型的磷脂，这是基本的类似脂肪的分子，有助于生成细胞膜(将细胞与周围环境隔离的屏障，也可以在细胞内形成内部隔间)。我们还将研究第三种影响神经系统的疾病，其临床特征与SPG81和SPG82相似，称为NEDMIMS，它是由肯尼迪途径中另一种编码酶的基因突变引起的。目前，我们对NEDMIMS和SPG81和82的病理机制缺乏了解，也没有有效的治疗方法。在这项建议中，我们将使用斑马鱼来模拟三种遗传条件(SPG81、SPG82和NEDMIMS)，以揭示疾病机制并测试新的潜在治疗策略。我们的初步工作表明，SPG82可以在斑马鱼身上得到忠实的模拟，头部尺寸减小，运动障碍，以及与患者相似的血脂变化。我们的初步实验将分析SPG81和NEDMIMS斑马鱼模型的物理特征，并结合脂肪类型和丰度的测量。在随后的实验中，我们将使用各种先进的方法对所有三种模型的神经系统进行详细分析，其中包括显微镜和对受影响的细胞类型、细胞成分和分子途径的广泛分析。这将使我们能够获得在疾病状态下发生的过程的详细的分子描述，从而确定涉及的病理机制。在项目的最后部分，我们将尝试各种方法来拯救疾病病理。这将包括基因方法，即我们重新表达受影响基因的“正常”副本，以及化学方法，即我们将用选定的药物或更大的药物库来治疗斑马鱼。这些挽救病理的治疗方法随后可能会在本奖项之后的进一步测试中被利用。重要的是，热休克本质上是渐进性的，因此有一个治疗窗口，使患者的治疗成为可能。这项工作很重要，因为它将确定三种高度衰弱的遗传疾病的机制，并允许确定新的潜在治疗方法。它也将与其他类似类型的神经疾病相关，包括更广泛的热休克蛋白，以及其他类型的运动神经元疾病。

The hereditary spastic paraplegias (HSP)s are a large group of debilitating genetic disorders that lead to lower limb weakness and stiffness (spasticity). Unfortunately, the condition progresses, leading to patients experiencing increasing difficulties. In some forms of HSP, symptoms are confined to the lower limbs, while other patients may suffer a wider range of medical problems (referred to as complex HSP). In this proposal we will investigate two complex forms of HSP, known as SPG81 and SPG82. These complex HSPs are caused by mutations in genes that encode enzymes of the so-called Kennedy pathway of lipid metabolism. This pathway makes two types of phospholipids, which are essential fat-like molecules that help generate cell membranes (barriers that enclose the cell from the surrounding environment and also make internal compartments inside the cell). We will also study a third disease that affects the nervous system, with similar clinical features to SPG81 and SPG82, called NEDMIMS, which is caused by mutations in another gene encoding an enzyme in the Kennedy pathway.Currently, we lack understanding of the pathological mechanisms of NEDMIMS and SPG81 and 82, and there are no effective treatments. In this proposal, we will use zebrafish to model the three genetic conditions (SPG81, SPG82 and NEDMIMS) to reveal disease mechanisms and test new potential therapeutic strategies. Our preliminary work indicates that SPG82 can be modelled faithfully in zebrafish, with reduced head size and defective movement, and changes in lipids similar to those seen in patients. Our initial experiments will perform the analysis of the physical features of the SPG81 and NEDMIMS zebrafish models, which will be combined with measurements of lipid types and abundance. In subsequent experiments we will carry out a detailed analysis of the nervous system in all 3 models using a variety of advanced approaches, which includes microscopy and an extensive analysis of the cell types, cellular components, and molecular pathways that are affected. This will allow us to obtain a detailed molecular description of the processes that occur in the disease state, and hence identify the pathological mechanisms involved. In the final part of the project we will try various approaches to rescue the disease pathology. This will include genetic approaches where we re-express a 'normal' copy of the affected gene, and chemical ones, where we will treat the zebrafish with selected drugs or a larger library of drugs. Those treatments that rescue the pathology may then be exploited in further testing that would follow on from this award. Importantly, the HSPs are progressive in nature and hence there is a therapeutic window, making treatment of patients possible. This work is important because it will identify the mechanisms of three highly debilitating genetic conditions, and allow the identification of new potential treatments for them. It will also have relevance for other similar types of neurological conditions, including the HSPs more generally, as well other types of motor neurone disease.