Mechanisms of cognitive deficits in dystroglycanopathies

 描述(申请人提供)：营养不良症是一组先天性肌营养不良症，涉及脑畸形和严重的智力低下。大多数已确定的原因是糖基转移酶的突变，导致细胞外基质受体α-肌营养不良聚糖的低糖基化。脑畸形，包括II型无脑畸形，被认为是一种神经元移行障碍，目前还没有有效的治疗方法。该项目的长期目标是开发基因治疗策略来改善大脑功能。令人惊讶的是，虽然异常的大脑结构被认为是神经功能障碍和紊乱的最关键因素，但我们最近的研究提供了令人信服的 有证据表明，许多关键的神经功能更关键地依赖于成人大脑中正在进行的糖基化。特别是，我们发现空间学习障碍主要是由于细胞-ECM相互作用缺陷导致树突棘可塑性改变所致，糖基化恢复可恢复脊柱可塑性并改善脑功能，尽管组织结构异常。因此，我们的假设是，尽管大脑畸形，但出生后的基因治疗可以恢复脊柱的可塑性，并改善大脑功能。这项建议侧重于空间学习障碍的机制和基因治疗的补救，作为改善血糖营养不良患者心理功能的第一步。具体目的是为了了解基因治疗导致空间学习障碍和功能恢复的机制。目的1：确定树突棘可塑性缺陷导致大鼠空间学习障碍的机制。 糖代谢不良症小鼠模型。目的2：确定尽管存在脑畸形，通过基因治疗恢复α-肌营养不良糖链糖基化是否能挽救糖尿病患者的空间学习能力。这项建议将研究空间学习缺陷的基础及其通过基因治疗的纠正，而不是使用组织学、电生理学、生化和最新的遗传学方法纠正迁移障碍本身。它将导致对疾病的更好理解，并有望产生实验性疗法。针对出生后可塑性缺陷而不是纠正发育组织缺陷的基因治疗策略可能对其他神经元迁移障碍具有广泛的实用价值。

 DESCRIPTION (provided by applicant): Dystroglycanopathies are a group of congenital muscular dystrophies that involve brain malformations and severe mental retardation. Most of the identified causes are mutations in glycosyltransferases that cause hypoglycosylation of a-dystroglycan, an extracellular matrix receptor. The brain malformations, including type II lissencephaly are characterized as a type of neuronal migration disorder, for which no effective therapy exists. The long-term goal of this project is to develop gene therapeutic strategies to improve brain function. Surprisingly while abnormal brain architecture is believed to be the most critical contributor to the neural dysfunction and disorders, our recent studies provide compelling evidence that a number of key neural functions depend more critically on ongoing glycosylation in the adult brain. In particular we have found that spatial learning insufficiency is mainly cause by altered dendritic spine plasticity due to defective cell-ECM interactions and that restoration o glycosylation restores spine plasticity and improves brain function despite abnormal histological structures. Therefore, our Hypothesis is that postnatal gene therapy restores spine plasticity and improves brain function despite the malformed brain. This proposal focuses on the mechanisms of spatial learning deficits and its rescue by gene therapy as a first step to improve mental function in dystroglycanopathies. The specific aims are designed to understand the mechanisms of spatial learning deficits and functional recovery by gene therapy. Aim 1: Determine the mechanisms of defective dendritic spine plasticity that contributes to spatial learning deficits in mouse models of dystroglycanopathies. Aim 2: Determine whether restoration of a-dystroglycan glycosylation by gene therapy rescues spatial learning in dystroglycanopathies despite the presence of brain malformations. This proposal will study the basis of spatial learning deficits and their correction via gene therapy without correcting the migration disorder itself using histological, electrophysiological, biochemical, and state-of-the-art genetic approaches. It will lead to improved understanding of the diseases and is expected to produce experimental therapies. The strategy of gene therapy targeted towards postnatal plasticity defects as opposed to correcting developmental histological defects may be broadly useful for other neuronal migration disorders.