Role of gangliosides in microglia biology

所有细胞的表面都装饰着糖，也称为聚糖，附着在膜蛋白和脂质上。由于其生物物理性质和结构多样性，聚糖在细胞间的通信以及细胞与其微环境之间的相互作用中发挥重要作用。 在大脑中，>80%的聚糖与脂质分子连接，而>75%的唾液酸-一种在细胞识别和细胞间通讯中特别重要的聚糖-包含在一类特殊的脂质中：神经节苷脂。大脑含有最多的这些脂质，它们几乎位于每个脑细胞的表面。这表明，在大脑中，神经节苷脂可能是与细胞间通讯相关的过程以及细胞与其微环境之间相互作用的主要参与者。研究表明，在神经元中，神经节苷脂调节与髓鞘的相互作用和各种细胞信号传导途径的活性。然而，对神经节苷脂在其他脑细胞中的功能知之甚少。其中，小胶质细胞，大脑的“免疫”细胞，不断地调查大脑环境和神经元的表面，以评估神经元的健康和完整性，并检测组织损伤或病原体的存在。根据遇到的特定刺激和信号，它们会做出各种活动的反应，其中可能包括迁移到受伤部位、释放保护性或有毒分子、消除细胞碎片或病原体以及修复损伤。 我们研究计划的首要假设是，神经节苷脂是小胶质细胞对大脑微环境的反应的重要调节剂，也是神经元和小胶质细胞之间串扰的关键介质。 我们假设：1）在小胶质细胞中表达的神经节苷脂调节这些细胞对神经元和环境线索的反应，并且这些反过来调节神经节苷脂的产生; 2）另一方面，在神经元表面上表达的神经节苷脂是被周围的小胶质细胞识别的“代码”的一部分，帮助它们“读取”神经元的健康状态并提供适当的反应。我们的研究计划将测试这些假设，并回答以下具体问题： 目的1）小胶质细胞对特定刺激的不同反应状态是否具有不同的神经节苷脂谱？反过来，这些变化如何调节小胶质细胞对其微环境的反应，以及后果是什么？ 目的2）神经元在健康和应激条件下是否暴露不同的神经节苷脂模式？这些变化如何影响与小胶质细胞的相互作用？ 我们的研究计划将填补一个重要的知识空白，并将导致更好地了解神经节苷脂在小胶质细胞生物学和脑细胞之间的通信中的作用。

The surface of all cells is decorated with sugars, also known as glycans, attached to membrane proteins and lipids. Due to their biophysical properties and structural diversity, glycans play important roles in the communication among cells and in the interaction between cells and their microenvironment. In the brain, >80% of glycans are linked to lipid molecules, and >75% of sialic acid - a glycan that is particularly important in cell recognition and cell-to-cell communication - is contained in one specific class of lipids: the gangliosides. The brain contains the largest amount of these lipids, which are located on the surface of almost every brain cell. This suggests that, in the brain, gangliosides might be major actors in processes linked to cell-to-cell communication and in the interaction between cells and their micro-environment. Research has shown that in neurons, gangliosides modulate the interaction with myelin and the activity of various cell signalling pathways. However, very little is known on the function of gangliosides in other brain cells. Among these, microglia cells, the “immune” cells of the brain, constantly survey the brain environment and the surface of neurons to assess neuronal health and integrity, and to detect the presence of tissue damage or pathogens. Depending on the specific stimulus and signals encountered, they respond with various activities, which may include migration to site of injury, release of protective or toxic molecules, elimination of cell debris or pathogens and repair of damage. The overarching hypothesis of our research program is that gangliosides are important modulators of the response of microglia cells to the brain microenvironment and key mediators in the crosstalk between neurons and microglia. We hypothesise that: 1) gangliosides expressed in microglia modulate the response of these cells to neuronal and environmental cues, and these, in turn, regulate ganglioside production; 2) on the other hand, gangliosides expressed on the surface of neurons are part of a “code” that is recognized by surrounding microglia, helping them to “read” the health status of neurons and provide an appropriate response. Our research program will test these hypotheses and will answer the following specific questions: Aim 1) Are different states of microglia in response to specific stimuli characterized by different ganglioside profiles? And in turn, how do these changes modulate microglia response to their microenvironment, and what are the consequences? Aim 2) Do neurons expose different patterns of gangliosides in healthy and stress conditions? And how do these changes affect the cross-talk with microglia? Our research program will fill an important gap in knowledge and will lead to a better understanding of the role of gangliosides in microglia biology and in the communication among brain cells.