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

摘要 遗传性痉挛截瘫(HSP)是一大群异质性神经遗传性疾病。 由皮质运动神经元轴突的长度依赖性退化引起。皮质运动神经元，一组 位于运动皮质的投射神经元，通过下层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的传递 大脑到脊髓，然后是肌肉，导致肌肉的渐进性痉挛和无力。 目前，仍缺乏有效的治疗方法来改善、停止或逆转 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 它们在脂类代谢中的作用。神经胶质细胞在脂质的生成和调节中起重要作用 大脑中的新陈代谢。然而，HSP脑内脂代谢是否发生改变，胶质细胞起什么作用 细胞在HSP发病机制中的作用在很大程度上还不清楚。这项拟议的研究的目标是剖析 脂代谢及神经胶质细胞与神经元相互作用在发病机制中的新作用 用SPG3A患者IPSCs来源的皮质神经元和神经胶质细胞共培养的方法检测HSP。 SPG3A是最常见的早发性HSP，由ATL-1基因突变引起 编码atlastin-1蛋白。我们将通过追求以下三个目标来验证我们的假设：1) 确定胶质细胞在SPG3A轴突和突触缺陷中的作用，2)确定其作用 SPG3A中神经胶质细胞在胆固醇稳态受损中的作用；3)挽救轴突和突触 SPG3A中的缺陷通过靶向受损的神经胶质细胞-神经元相互作用来实现。通过比较皮质细胞的共培养 神经元与正常或SPG3A神经胶质细胞，我们的研究将提供深入了解神经胶质细胞在 热休克蛋白。Atlastin-1突变和轴突表型之间的因果关系将是 通过挽救SPG3A ipscs的突变和敲击正常人类的突变而得到确认 多能干细胞。此外，还将进行救援实验，以确定可能的方法 通过调节神经胶质细胞的脂质代谢，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和HSP发病机制中的新作用。 确定热休克治疗干预的新靶点。

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.