Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD

拉福拉病(LD)是一种致命性、隐性神经退行性疾病，表现为癫痫事件。 生命的第二个十年。LD的一个特征是细胞质中积累的过度磷酸化的水-- 不溶的类糖原颗粒称为拉福拉小体(LBS)。LD是由这两个基因中的任何一个的突变引起的 编码糖原磷酸酶Laforin或E3泛素连接酶Malin的基因，以及这两个基因的突变都会导致 在LD的发展过程中。由于神经元对能量的敏感性，LBS引起急性神经毒性而致病 微扰。与Lb形成相关的细胞显示多个标记，指示临界状态下的扰动 细胞途径，包括内质网应激增加、自噬、ROS产生等。 该计划项目赠款的总体重点是促进Lafora癫痫治疗倡议(LECI)： 这是一个致力于LD的诊断、治疗和治疗的国际合作组织。这样做的目的是 项目是定义LD突变的临床生物化学，以提供个性化诊断并建立 治疗选择。为了实现这些目标，我们将利用结构定义LD的分子基础 生物化学、细胞生物学和小鼠模型，并将我们的见解转化为突变特异性诊断 以及改善LD所致癫痫、治愈LD的新的治疗方法。 我们将首先使用集成的结构和功能工具来定义物理和细胞扰动 由Laforin和Malin的LD突变引起。这些方法将使我们能够定义 神经元特异性毒性导致疾病。然后，我们将开发个性化的诊断方法和 治疗LD患者。我们将确定神经递质转运体在LD中的作用。此外，我们还将 确定拉福林和马林如何影响转运体稳态以及LD小鼠模型对 用抗癫痫药物治疗症状。最后，我们将确定药理作用的有益作用 干预促进提前终止密码子通读的新型化合物。嵌入在这些 方法是开发一种新的生物检测方法，将允许对患者进行特定诊断和定义 疾病的分子亚型，是莱西中心每个项目的关键。此外，这些结果还具有 由于LD是五种主要的进行性肌阵挛癫痫之一，因此具有更广泛的意义， 代谢功能障碍和癫痫之间的联系是一个新兴的主题。 累积起来，这些结果将允许个性化的治疗选择，这些选择是为了促进 分子和细胞功能的恢复是治疗和治疗LD的一种手段。

Lafora disease (LD) is a fatal, recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic, hyperphosphorylated, water- insoluble glycogen-like particles called Lafora bodies (LBs). LD results from mutations in either of the genes encoding laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase, and mutations in either gene results in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. Associated with LB formation, cells display multiple markers indicating perturbations in critical cellular pathways, including increased endoplasmic reticulum stress, autophagy, ROS production, and others. The overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): which is an international collaboration devoted to the Diagnosis, Treatment, and Cure of LD. The goals of this project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options. To achieve these goals, we will define the molecular basis of LD utilizing structural biochemistry, cellular biology, and mouse models and translate our insights into mutation-specific diagnoses and novel therapeutic approaches to ameliorate LD induced epilepsy and cure LD. We will first utilize integrated structural and functional tools to define the physical and cellular perturbations caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and treat LD patients. We will define the role of neurotransmitter transporters affected in LD. Further, we will determine how laforin and malin affect transporter homeostasis and how LD mouse models respond to treatment of symptoms with antiepileptic drugs. Lastly, we will establish the beneficial effect of pharmacological intervention novel compounds that promote read-through of premature termination codons. Embedded in these approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of molecular sub-types of the disease, key to each of the LECI Center projects. Further, these results have significant broader implications since LD is one of five major progressive myoclonic epilepsies, and the connection between metabolic dysfunction and epilepsy is an emerging theme. Cumulatively, these results will allow personalized therapeutic options that are developed to promote recovery of molecular and cellular function as a means of treating and curing LD.