Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
J Neurochem. 2021 Mar;156(6):819-833. doi: 10.1111/jnc.15137. Epub 2020 Aug 13.
Ganglioside GD3, a major ganglioside species in neural stem cells, plays a crucial role in maintenance of the self-renewal capacity of these cells. However, its bioactivity in postnatally differentiated neurons in the neurogenic regions of adult brains has not been elucidated. Here, we describe for the first time that deletion of GD3 not only impairs neurotrophin-induced stem cell proliferation, but also alters the dendritic structure as well as the number of synapses of nascent neurons in the dentate gyrus of adult brain. When examining the behavioral phenotypes, GD3 synthase-knockout (GD3S-KO) mice displayed impairment in hippocampus-dependent memory function. To further gain insight into its cellular function, we examined GD3-binding partners from mouse brain extract using a GD3-specific monoclonal antibody, R24, followed by LC-MS/MS analysis and identified a mitochondrial fission protein, the dynamin-related protein-1 (Drp1), as a novel GD3-binding protein. Biochemical and imaging analyses revealed mitochondrial fragmentation in GD3-depleted dentate gyrus neurons, suggesting that GD3 is essential for the mitochondrial Drp1 turnover that is required for efficient mitochondrial fission. These results suggest that GD3 is required for proper dendritic and spine maturation of newborn neurons in adult brain through the regulation of mitochondrial dynamics.
神经节苷脂 GD3 是神经干细胞中主要的神经节苷脂种类，在维持这些细胞的自我更新能力方面发挥着关键作用。然而，其在成年大脑神经发生区域中已分化神经元中的生物活性尚未阐明。在这里，我们首次描述了 GD3 的缺失不仅会损害神经营养因子诱导的干细胞增殖，还会改变成年大脑齿状回中新生神经元的树突结构和突触数量。在研究行为表型时，GD3 合成酶敲除（GD3S-KO）小鼠表现出海马依赖型记忆功能障碍。为了进一步深入了解其细胞功能，我们使用针对 GD3 的单克隆抗体 R24 从鼠脑提取物中检测 GD3 结合蛋白，然后进行 LC-MS/MS 分析，鉴定出一种线粒体分裂蛋白，即与动力相关蛋白 1（Drp1）作为一种新型的 GD3 结合蛋白。生化和成像分析显示，GD3 耗尽的齿状回神经元中线粒体碎片化，表明 GD3 对于线粒体 Drp1 周转是必需的，这对于有效的线粒体分裂是必需的。这些结果表明，GD3 通过调节线粒体动力学，对于成年大脑中新神经元的树突和棘突成熟是必需的。
