Role of gangliosides in microglia biology

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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.