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

总结 遗传性痉挛性截瘫（HSP）是一个大的异质性组的神经遗传性疾病引起的 皮层运动神经元轴突的长度依赖性变性。皮质运动神经元，一组 位于运动皮层的投射神经元，通过下运动神经元控制肌肉运动， 脑干和脊髓这些神经元的退化中断了信号从 大脑到脊髓，然后是肌肉，导致肌肉进行性痉挛和无力。 目前，仍然缺乏有效的治疗方法来改善，停止或逆转轴突缺陷， 热休克蛋白最近的研究表明，几种HSP蛋白可以调节脂滴的大小，这意味着 它们在脂质代谢中的作用胶质细胞在脂质的生成和调节中起重要作用 大脑的新陈代谢。然而，HSP脑内脂质代谢是否发生改变以及胶质细胞在HSP脑内的作用如何， 细胞在HSP发病机制中的作用在很大程度上是未知的。这项研究的目的是解剖 脂质代谢的新作用以及神经胶质细胞和神经元之间的相互作用在发病机制中 使用源自SPG 3A患者的iPSC的皮质神经元和神经胶质细胞的共培养物的HSP。 SPG 3A是由ATL-1基因突变引起的最常见的早发型HSP， 编码atlastin-1蛋白。我们将通过追求以下三个目标来测试我们的假设：1） 确定神经胶质细胞对SPG 3A中轴突和突触缺陷的贡献，2）确定神经胶质细胞在SPG 3A中的作用， SPG 3A中受损胆固醇稳态中的胶质细胞，和3）拯救轴突和突触 SPG 3A的缺陷通过靶向受损的神经胶质-神经元相互作用。通过比较皮层神经元 神经元与正常或SPG 3A胶质细胞，我们的研究将提供深入了解胶质细胞在神经元中的作用， 过敏性紫癜。atlastin-1突变和轴突表型之间的因果关系将是 通过拯救SPG 3A iPSC中的突变并通过将突变敲入正常人细胞中来证实 多能干细胞此外，将进行救援实验以确定潜在的方法 通过调节神经胶质细胞的脂质代谢来减轻HSP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发病机制中的新作用， 确定HSP治疗干预的新靶点。

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.