Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Adv Neurobiol. 2023;29:281-304. doi: 10.1007/978-3-031-12390-0_10.
Gangliosides are sialylated glycosphingolipids (GSLs) with essential but enigmatic functions in brain activities and neural stem cell (NSC) maintenance. Our group has pioneered research on the importance of gangliosides for growth factor receptor signaling and epigenetic regulation of NSC activity and differentiation. The primary localization of gangliosides is on cell-surface microdomains and the drastic dose and composition changes during neural differentiation strongly suggest that they are not only important as biomarkers, but also are involved in modulating NSC fate determination. Ganglioside GD3 is the predominant species in NSCs and GD3-synthase knockout (GD3S-KO) revealed reduction of postnatal NSC pools with severe behavioral deficits. Exogenous administration of GD3 significantly restored the NSC pools and enhanced the stemness of NSCs with multipotency and self-renewal. Since morphological changes during neurogenesis require a huge amount of energy, mitochondrial functions are vital for neurogenesis. We discovered that a mitochondrial fission protein, the dynamin-related protein-1 (Drp1), as a novel GD3-binding protein, and GD3 regulates mitochondrial dynamics. Furthermore, we discovered that GM1 ganglioside promotes neuronal differentiation by an epigenetic regulatory mechanism. Nuclear GM1 binds with acetylated histones on the promoters of N-acetylgalactosaminyltransferase (GalNAcT; GM2 synthase) as well as on the NeuroD1 genes in differentiated neurons. In addition, epigenetic activation of the GalNAcT gene was detected as accompanied by an apparent induction of neuronal differentiation in NSCs responding to an exogenous supplement of GM1. GM1 is indeed localized in the nucleus where it can interact with transcriptionally active histones. Interestingly, GM1 could induce epigenetic activation of the tyrosine hydroxylase (TH) gene, with recruitment of nuclear receptor related 1 (Nurr1, also known as NR4A2), a dopaminergic neuron-associated transcription factor, to the TH promoter region. In this way, GM1 epigenetically regulates dopaminergic neuron specific gene expression. GM1 interacts with active chromatin via acetylated histones to recruit transcription factors at the nuclear periphery, resulting in changes in gene expression for neuronal differentiation. The significance is that multifunctional gangliosides modulate lipid microdomains to regulate functions of important molecules on multiple sites: the plasma membrane, mitochondrial membrane, and nuclear membrane. Versatile gangliosides could regulate functional neurons as well as sustain NSC functions via modulating protein and gene activities on ganglioside microdomains.
神经节苷脂是唾液酸化的糖脂（GSLs），在大脑活动和神经干细胞（NSC）维持中具有重要但神秘的功能。我们的团队开创了研究神经节苷脂对生长因子受体信号转导和 NSC 活性和分化的表观遗传调控的重要性的先河。神经节苷脂的主要定位是在细胞膜表面微区，并且在神经分化过程中神经节苷脂的浓度和组成发生剧烈变化，这强烈表明它们不仅是重要的生物标志物，而且还参与调节 NSC 命运决定。神经节苷脂 GD3 是 NSCs 中的主要物质，GD3 合成酶敲除（GD3S-KO）导致出生后 NSC 池减少，伴有严重的行为缺陷。外源性 GD3 的给药显著恢复了 NSC 池，并增强了 NSC 的多能性和自我更新能力。由于神经发生过程中的形态变化需要大量的能量，线粒体功能对神经发生至关重要。我们发现，一种线粒体分裂蛋白，即与 dynamin 相关的蛋白 1（Drp1），作为一种新型的 GD3 结合蛋白，GD3 调节线粒体动力学。此外，我们发现 GM1 神经节苷脂通过表观遗传调控机制促进神经元分化。核 GM1 与 N-乙酰半乳糖胺转移酶（GalNAcT；GM2 合酶）启动子上的乙酰化组蛋白以及分化神经元中的 NeuroD1 基因结合。此外，在外源性 GM1 补充时，NSC 中检测到 GalNAcT 基因的表观遗传激活，伴随着明显的神经元分化诱导。GM1 确实定位于细胞核内，在那里它可以与转录活跃的组蛋白相互作用。有趣的是，GM1 可以诱导酪氨酸羟化酶（TH）基因的表观遗传激活，将核受体相关 1（Nurr1，也称为 NR4A2）募集到 TH 启动子区域，Nurr1 是一种多巴胺能神经元相关转录因子。通过这种方式，GM1 在外周核中通过乙酰化组蛋白与活性染色质相互作用，募集转录因子，导致多巴胺能神经元特异性基因表达的变化。GM1 通过与乙酰化组蛋白相互作用，在核周招募转录因子，在核周改变与神经元分化相关的基因表达。其意义在于，多功能神经节苷脂调节脂质微区，以调节多个部位（细胞膜、线粒体膜和核膜）上重要分子的功能。多功能神经节苷脂可以通过调节神经节苷脂微区上的蛋白质和基因活性来调节功能性神经元和 NSC 功能。
