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Role of atlastin-1 in axonal development and degeneration of human neurons

atlastin-1 在人类神经元轴突发育和变性中的作用

基本信息

批准号：
9259640
负责人：
XUE-JUN LI
金额：
$ 14.36万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2016-04-15 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9259640
关键词：
Role atlastin axonal development degeneration

项目摘要

DESCRIPTION (provided by applicant): Impaired axonal development and degeneration are implicated in many debilitating disorders, such as hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and periphery neuropathy. HSP is caused by distal axonopathy involving the longest corticospinal tract axons, leading to spasticity and weakness of the lower extremities. The most common early-onset form of HSP, SPG3A, is caused by mutations in the atlastin-1 gene. This gene encodes atlastin-1 protein, which is a member of the dynamin-related large GTPase superfamily. Knockdown of atlastin-1 in rat cortical neuron in vitro cultures inhibits the axonal outgrowth and elongation. However, how altered atlastin-1 activity leads to axonal defects and why specific axons degenerate in HSP patients are largely unclear. The goal of this proposed study is to establish human neuronal models of SPG3A to delineate the mechanisms underlying the axonal defects in HSP. This study's hypothesis is that atlastin mutations result in axonal defects selectively in cortical projection neurons (cortical PNs), and this effect is mediated mainly by dysregulated bone morphogenetic protein (BMP) signaling. This hypothesis will be tested by pursuing the following two aims: 1) to examine the axonal outgrowth and transport in cortical PNs derived from iPSCs that are generated from SPG3A patients and normal individuals (as controls); 2) to delineate the role of BMP signaling in the axonal defects in SPG3A. By comparing the axonal defects, atlastin-1 activity, and BMP signaling alterations in cortical PNs, cortical interneurons, and spinal motor neurons derived from control and SPG3A iPSCs, this study will be able to delineate the cell type-specific defects in HSP and the underlying mechanisms. The cause-effect relationship between loss of atlastin function and axonal phenotypes will be confirmed by knocking down atlastin-1 in wild-type (WT) neurons and by expressing WT atlastin-1 in SPG3A iPSCs. Moreover, rescue experiments will be performed to identify the potential approaches for rescuing the axonal pathology, such as overexpression of atlastin or treatment with BMP antagonists. Together, this study will provide valuable insights into the roles of atlastin-1 and BMP signaling in HSP pathology and developing new therapeutics for rescuing the axonal degeneration in HSP.

描述（由申请人提供）：轴突发育和变性受损与许多衰弱性疾病有关，如遗传性痉挛性截瘫（HSP）、肌萎缩侧索硬化症和周围神经病变。HSP是由远端轴突病引起的，涉及最长的皮质脊髓束轴突，导致下肢痉挛和无力。最常见的早发型热休克，SPG3A，是由atlastin-1基因突变引起的。该基因编码atlastin-1蛋白，该蛋白是与动力蛋白相关的大GTPase超家族的成员。敲低atlastin-1对体外培养大鼠皮层神经元的抑制作用