Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD

Lafora病（LD）是一种致命的隐性神经退行性疾病，表现为癫痫事件， 人生的第二个十年LD的一个标志是细胞质中过度磷酸化的水- 不溶性糖原样颗粒，称为Lafora小体（LB）。LD是由两个基因中的任何一个突变引起的 编码laforin（一种糖原磷酸酶）或malin（一种E3泛素连接酶），并且任一基因的突变导致 在发展LD。由于神经元对能量的敏感性，LB会导致急性神经毒性疾病 扰动与LB形成相关，细胞显示多个标志物，指示关键细胞中的扰动。 细胞途径，包括增加内质网应激、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诊断、治疗和治愈的国际合作组织。这个的目标 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，我们将利用结构确定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诱发的癫痫和治疗LD的新的治疗方法。 我们将首先利用集成的结构和功能工具来定义物理和细胞扰动 由拉福林和马林的LD突变引起。这些方法将使我们能够确定 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， 治疗LD患者。我们将确定的作用，神经递质转运蛋白在LD的影响。此外，我们将 确定laforin和malin如何影响转运蛋白稳态以及LD小鼠模型如何响应 用抗癫痫药物治疗症状。最后，我们将建立药理学的有益效果， 干预促进提前终止密码子通读的新化合物。内嵌其中 一种新的生物测定方法的发展将允许患者特异性诊断和定义 分子亚型的疾病，关键的每个LECI中心项目。此外，这些结果具有 由于LD是五种主要的进行性肌阵挛性癫痫之一， 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，这些结果将允许开发个性化的治疗选择，以促进 分子和细胞功能的恢复作为治疗和治愈LD的手段。

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.