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Defining the Role of Laforin in Glycogen Metabolism and Lafora Disease

定义 Laforin 在糖原代谢和 Lafora 疾病中的作用

基本信息

批准号：
9298391
负责人：
Mary Kathryn Brewer
金额：
$ 3.51万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298391
关键词：
Address Adolescence Affect Affinity Architecture Binding Biological Assay Brain Carbohydrates Cessation of life Clinical Research Crystallization Cystic Fibrosis Data Diabetes Mellitus Diagnosis Dimerization Disease Disease Progression Enzymes Epilepsy Event Family Genes Genetic Glucans Glucose Glycogen Goals Heterogeneity Homeostasis Human Hybrids Impaired cognition Investigation Knockout Mice Lafora Disease Lead Length Light Linear Models Malignant Neoplasms Mammals Maps Metabolic Diseases Missense Mutation Molecular Mutation Nature Nerve Degeneration Neurologic Neurologic Symptoms Neurons Oligosaccharides Onset of illness Outcome Patients Phenotype Phosphoric Monoester Hydrolases Phosphorylation Play Point Mutation Positioning Attribute Potassium Glutamate Progressive Myoclonic Epilepsies Protein Dephosphorylation Proteins Publishing Regulation Reporting Role Seizures Solubility Source Specificity Structure Techniques Textbooks Time Tissues biochemical tools biophysical tools brain metabolism carbohydrate metabolism design dimer extracellular falls gain of function mutation glycogen metabolism inorganic phosphate insight member mouse model mutant nervous system disorder neurotoxic particle

项目摘要

Project Summary/Abstract The goal of this proposal is to use the unique window offered by Lafora disease (LD) to understand how laforin regulates glycogen metabolism and define the molecular perturbation of LD patient mutations. Lafora disease (LD), one of the five major progressive myoclonus epilepsies, is a fatal, genetic, neurological disorder that manifests during adolescence and invariably leads to neurodegeneration and death. Patients with LD display accumulations of hyperphosphorylated, aberrantly branched, glycogen-like particles called Lafora bodies (LBs). LBs are found in most tissues but neurological symptoms predominate in LD patients. Mutations in the gene encoding the glycogen phosphatase laforin cause approximately 70% of LD cases. LD largely centers on glycogen metabolism. Glycogen is the most important carbohydrate storage molecule in mammals, and misregulation of glycogen is implicated in many diseases. Recent studies show that glycogen plays a dynamic role in brain function and that neurons are highly sensitive to glycogen perturbations. Although glycogen has been studied for many years, gaps in our understanding of its regulation remain. The Gentry lab established laforin as the founding member of the glucan phosphatase family (i.e. enzymes that release phosphate from carbohydrates), and studies on LD show that the absence of laforin triggers the transformation of glycogen into the neurotoxic carbohydrate that makes up LBs. As the only glucan phosphatase in humans, laforin is the lynchpin of glycogen regulation by phosphorylation. We recently determined the crystal structure of laforin. This proposal will couple insights from the structure with biochemical and biophysical tools to define how laforin functions as a glucan phosphatase and regulates glycogen metabolism. Further, the 33 LD-associated missense mutations are scattered throughout the structure and have different effects on laforin activity. A goal in our lab is to define the effect of all of these mutations. Aim 1A will address the nature of the dimer interface, which has been controversial in the field, and the molecular effect of LD mutations in this region. Aim 1B will define how laforin cooperatively binds the glucan chains in glycogen and the effects of length and branching. Aim 2 will establish the role of the interdomain region of laforin (i.e. between the phosphatase and carbohydrate-binding domains) in maintaining C3- and C6-specific dephosphorylation of glycogen. A number of LD mutations fall in this region and this aim will demonstrate their functional effects. In summary, this proposal utilizes cross-disciplinary techniques to study glycogen homeostasis and the mechanisms of LD, studies that will provide insights into brain metabolism and pave the way for patient-specific diagnoses and treatments.

项目总结/文摘