THE CONNECTION BETWEEN LAFORA DISEASE AND OTHER POLYGLUCOSAN BODY DISEASES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Lafora病（LD）是由碳水化合物磷酸酶laforin突变引起的。 LD的一个标志是不溶性碳水化合物（称为Lafora小体（LB））在细胞质中的积累。 虽然LB在大多数细胞中积累，但凋亡仅发生在神经元中，这最终导致癫痫和患者死亡。 预激-帕金森-白色综合征（WPW）是由细胞能量传感器和调节器AMP-活化蛋白激酶（AMPK）突变引起的不溶性碳水化合物积聚引起的心脏肥大。 麦卡德尔病（GSD V）是一种糖原储存疾病，其导致肌肉中糖原储存增加，这是由编码肌肉糖原磷酸化酶的PYGM基因突变引起的。 安德森氏病（GSD IV）是由糖原分支酶突变引起的，并导致异常糖原储存，特别是在肝脏和心脏中。 该提案将定义事件，并确定LD和其他涉及葡聚糖积累的疾病之间的联系。 特异性目标1将鉴定LD蛋白和相互作用蛋白的修饰。 在具体目标2中，我们将确定翻译后修饰是否影响laforin与已知底物的结合、laforin的定位和/或laforin的磷酸酶。 在具体目标3中，我们将确定碳水化合物刺激AMPK激酶活性的机制。 在此过程中，我们将定义AMPK-激酶活性、碳水化合物催化剂和受影响的底物的倍数增加。 最后，我们将把这些发现转化为LD的小鼠模型。 拟议的研究将确定Lafora病和其他葡聚糖身体疾病之间的联系。 此外，他们将更好地表征碳水化合物代谢，这是包括糖尿病在内的多种代谢紊乱的核心，并对新的治疗方法产生见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lafora disease (LD) is caused by mutations in the carbohydrate phosphatase laforin. A hallmark of LD is the accumulation of insoluble carbohyrate, called Lafora bodies (LBs), in the cytoplasm of cells. While LBs accumulate in most cells, apoptosis only occurs in neurons and this eventually leads to epilepsy and death of the patient. Wolff-Parkinson-White (WPW) syndrome is a cardiac hypertrophy caused by insoluble carbohydrate accumulations resulting from mutations in the cellular energy sensor and regulator AMP-activated protein kinase (AMPK). McArdle's disease (GSD V) is a glycogen storage disease that results in increased glycogen storage in muscle caused by mutations in the PYGM gene that encodes muscle glycogen phosphorylase. Andersen's disease (GSD IV) is caused by mutations in glycogen branching enzyme and results in aberrant glycogen storage especially in the liver and heart. This proposal will define the events and determine the connection between LD and other diseases involving polyglucosan accumulations. Specific Aim 1 will identify modification of LD proteins and interacting proteins. In specific Aim 2, we will determine if post-translation modification affects laforin binding to known substrates, the localization of laforin, and/or the phosphatase of laforin. In specific aim 3, we will determine the mechanism of carbohydrate stimulated AMPK kinase activity. In doing so, we will define the fold increase in AMPK-kinase activity, the carbohydrate(s) catalyst, and the substrates affected. Finally, we will translate these findings into a mouse model of LD. The studies proposed will define connections between Lafora disease and other polyglucosan body disorders. In addition, they will better characterize carbohydrate metabolism, which is at the heart of multiple metabolic disorders including diabetes, and yield insights into novel treatments.