GM2+Ganglioside+and+Sphingolipidoses+Pathway



Tay-Sachs disease is caused by a build up of GM2 gangliosides in nerve and brain cells. This makes it seem as though gangliosides are some poison or toxic substances that no one would ever want in their body. However, gangliosides are actually normal, vital components of the plasma membranes of neuronal cells (Sandhoff, K. & Harzer, K., 2013). Gangliosides are molecules made up of a glycoshingolipid (a compound consisting of a ceramide, a waxy lipid, and an oligosaccharide, a small sugar chain) and one or more sialic acids (any of a group of N- or O- substituted neuraminic acid derivatives). Although they are found in various cell types, they are named ganglio-sides because they are predominantly found in the nervous system. The molecules are found integrated in the cell membrane, with the ceramide portion of the glycosphingolipid anchored into the cell wall with the oligosaccharide located outside of the cell in the extracellular space.

Gangliosides act as "identification badges" for cells, with the oligosaccharide portions sticking out of the cell being used as specific determinants for cell recognition. These compounds are also used in cell-to-cell communication/signaling and also play a role in cell growth/metabolism and differentiation. Recent evidence also suggests that gangliosides have a significant role in immunology and carcinogenesis (Bisel, B., Pavone, F.S., & Calamai, M., 2014).



Much like other lipids, such as LDL, HDL, and cholesterol (which are all also necessary components of cells, but, in excess, lead to other diseases), gangliosides are constantly synthesized and broken down in cells. Ganglioside degradation takes place within lysosomes in cells, which act like microscopic intracellular "stomachs," containing digestive enzymes that break apart small molecules much like our actual stomachs break down food. GM2 gangliosides are absorbed into the cell by a process known as clathrin-dependent endocytosis. This process involves the invagination, or "caving in" of a portion of the cell membrane, in this case, a portion containing the GM2 ganglioside. Utilizing a protein known as clathrin to make a sort of lattice bound case, the cell membrane forms a pit, containing the ganglioside, which closes into a ball-like structure as it is pinched off from the membrane within the cell. As the ball enters the cell, it is opened up and turned inside out, exposing the gangliosides, and taken to the lysosome.

In the lysosome, the gangliosides are embedded in the luminal lysosomal membrane, which is the inner wall of the lysosome (facing the open space inside the body of the lysosome). Here, the gangliosides are exposed to enzymatic proteins. The protein that is capable of breaking down GM2 gangliosides is beta-hexosaminidase A (or just hexosaminidase A). The protein is made up of two subunits, or parts, simply named alpha and beta. The alpha subunit is the only portion capable of degrading GM2 gangliosides, doing so through hydrolysis. However, for the alpha subunit to work, it needs the ganglioside to bound to an activator protein, aptly named GM2A Activating Protein (GM2-AP). GM2-AP acts a sort of "work bench" for the alpha subunit of hexosaminidase A, bring the ganglioside and the hexosaminidase enzyme together in the proper configuration. But to complicate matters further, the alpha subunit of hexosaminidase A is not capable of binding to GM2-AP on its own. Only the beta subunit of hexosaminidase A can bind to GM2-AP to activate the alpha subunit. This means that there are three necessary components to break down GM2 gangliosides that enter the cell, the alpha subunits of hexosaminidase A, the beta subunit of hexosaminidase A, and the GM2 Activating Protein.



When genetic mutations cause some of these enzymes to be absent, or not work, it results in partially or fully undigested gangliosides. As the gangliosides are continuously produced, if they are not being fully broken down, they begin to build up (Sandhoff, K. & Harzer, K., 2013). Anyone who has played Tetris and failed to fit pieces together to "digest" lines knows how this end -- "Game Over." As the gangliosides accumulate, they start impacting normal cellular function, preventing or halting development at the cellular level, ultimately destroying the cell.