Uncover the role of glia-neuron crosstalk in hereditary spastic paraplegias

揭示神经胶质-神经元串扰在遗传性痉挛性截瘫中的作用

基本信息

批准号：
10618808
负责人：
XUE-JUN LI
金额：
$ 37.58万
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：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618808
关键词：
ATP binding cassette transporter 1 Adipose tissue Agreement Alzheimer&apos s Disease Astrocytes Axon Axonal Transport Brain Brain Stem Caenorhabditis elegans Cells Cerebral cortex Cholesterol Cholesterol Homeostasis Coculture Techniques Corticospinal Tracts Cultured Cells Data Defect Development Disease Drosophila genus Electrophysiology (science)Endoplasmic Reticulum Exhibits Fat Body Genes Goals Hereditary Spastic Paraplegia Histologic Impairment In Vitro Induced pluripotent stem cell derived neurons Interruption Intestines Knock-in Knockout Mice Length Lipids Lipoproteins Mediating Modeling Morphogenesis Morphology Motor Cortex Motor Neurons Movement Muscle Muscle Spasticity Muscle Weakness Mutation Nerve Nerve Degeneration Neuroglia Neurons Pathogenesis Pathologic Processes Pathology Patients Phenotype Play Proteins Rodent Model Role Signal Transduction Source Spinal Spinal Cord Synapses Testing Therapeutic Therapeutic Intervention Vertebral column Zebrafish axonal degeneration axonopathy cholesterol trafficking early onset effective therapy experimental study fly human pluripotent stem cell in vivo induced pluripotent stem cell insight lipid metabolism locomotor deficit nervous system disorder neurogenetics new therapeutic target novel pharmacologic spasticity stem cell model trafficking transmission process

项目摘要

SUMMARY Hereditary spastic paraplegia (HSP) is a large heterogeneous group of neurogenetic disorders caused by the length-dependent degeneration of cortical motor neuron axons. Cortical motor neurons, a group of projection neurons located in motor cortex, control muscle movement through lower motor neurons in the brain stem and spinal cord. Degeneration of these neurons interrupts the signal transmission from brain to spinal cord and then muscles, resulting in progressive spasticity and weakness in muscles. Currently, there remains a lack of effective treatment to ameliorate, stop, or reverse axonal defects in HSPs. Recent studies show that several HSP proteins can regulate the size of lipid droplets, implying their roles in lipid metabolisms. Glial cells play an important for generating and regulating lipid metabolism in the brain. However, whether lipid metabolism is altered in HSP brain and what role glial cells play in the pathogenesis of HSP are largely unknown. The goal of this proposed study is to dissect the novel role of lipid metabolism and the interplay between glial cells and neurons in the pathogenesis of HSP using co-cultures of cortical neurons and glial cells derived from iPSCs of SPG3A patients. SPG3A is the most common early-onset form of HSP caused by mutations in the ATL-1 gene that encodes atlastin-1 protein. We will test our hypotheses by pursuing the following three aims: 1) to identify the contribution of glial cells to axonal and synaptic defects in SPG3A, 2) to determine the role of glial cells in impaired cholesterol homeostasis in SPG3A, and 3) to rescue axonal and synaptic defects in SPG3A by targeting the impaired glia-neuron interaction. By comparing co-cultures of cortical neurons with normal or SPG3A glial cells, our study will provide insights into the role of glial cells in HSP. The cause-effect relationship between atlastin-1 mutations and axonal phenotypes will be confirmed by rescuing the mutations in SPG3A iPSCs and by knocking in mutations to normal human pluripotent stem cells. Moreover, rescue experiments will be performed to identify potential approaches for mitigating axonal and synaptic defects in HSP through regulating lipid metabolism in glial cells. Together, our study is expected to reveal novel roles of glial cells in the pathogenesis of HSP and identify new targets for therapeutic intervention in HSP.

概括遗传性痉挛性截瘫（HSP）是引起的一组巨大的神经遗传疾病。根据皮质运动神经元轴突的长度依赖性变性。皮质运动神经元，一组位于运动皮层中的投射神经元，控制肌肉通过下部运动神经元运动脑干和脊髓。这些神经元的变性会中断信号传递大脑到脊髓，然后是肌肉，导致肌肉的进行性痉挛和无力。目前，仍然缺乏有效的治疗方法来改善，停止或反向轴突缺陷 HSP。最近的研究表明，几种HSP蛋白可以调节脂质液滴的大小，这意味着它们在脂质代谢中的作用。神经胶质细胞对于产生和调节脂质很重要大脑中的代谢。但是，脂质代谢是否在HSP大脑中发生改变以及何种作用神经胶质细胞在HSP的发病机理中发挥作用，在很大程度上未知。这项拟议的研究的目的是剖析脂质代谢的新作用以及神经胶质细胞与神经元之间的相互作用在发病机理中使用SPG3A患者IPSC的皮质神经元和神经胶质细胞共培养的HSP。 SPG3A是由ATL-1基因突变引起的最常见的早期发作形式，编码atlastin-1蛋白。我们将通过追求以下三个目标来检验我们的假设：1）确定神经胶质细胞对SPG3A中轴突和突触缺损的贡献，2）确定作用 SPG3A中胆固醇稳态受损的神经胶质细胞的摄取，3）挽救轴突和突触 SPG3A中的缺陷通过靶向神经胶质神经元相互作用受损。通过比较皮质的共培养神经元正常或SPG3A神经胶质细胞，我们的研究将提供有关神经胶质细胞在 HSP。 Atlastin-1突变与轴突表型之间的原因效应关系将是通过拯救SPG3A IPSC中的突变并将突变撞到正常人中确认多能干细胞。此外，将进行救援实验以识别潜在方法通过调节神经胶质细胞中的脂质代谢，用于减轻HSP中的轴突和突触缺陷。总之，我们的研究有望揭示神经胶质细胞在HSP和HSP发病机理中的新作用确定HSP治疗干预的新目标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.

DOI：
10.1016/j.nbd.2023.106293
发表时间：
2023-10-15
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Chai, Eric;Chen, Zhenyu;Mou, Yongchao;Thakur, Gitika;Zhan, Weihai;Li, Xue-Jun
通讯作者：
Li, Xue-Jun

Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients.