Enzyme Degradation Triggers Hereditary Storage Diseases

Lysosomes take over the function of the stomach in living cells. They digest superfluous metabolic products and break them down into their components; which are then available for the cell’s urgently needing new building; and operating materials as part of the recycling process. If digestion in the lysosomes is blocking; for example as a result of genetic defects; this cell waste is storage.

The growing mountain of waste materials can be toxic to nerve cells and may resulting in an early death; even in childhood. The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis); with GM2 as the major lysosomal storage compound.

Hereditary storage diseases

But the ganglioside GM2 being storing in the lysosomes. Gangliosides are water insoluble fats, so called lipids, which occur mainly in the ganglion cells of the nervous system. If the GM2 degrading enzyme Hex A is missing or impairing, for example due to genetic defecting; destructive ganglioside storage occurs.

Affecting children develop normally in the first months of life; later on, blindness, movement restrictions; and mental decline occur and eventually an early death. Previous therapeutic approaches have not led to any significant successes in these neurodegenerative gangliosidoses. Enzyme replacement therapies have failing due to the impermeability of the blood-brain barrier for these substances.

Molecular environment in lysosome

But the molecular environment in the lysosome for the successful degradation of GM2. In the test tube; the scientists reconstructed the tiny bubbles (vesicles); on which the GM2 is degrading in the “cell stomach” (the lysosome). Normally, the auxiliary protein GM2AP helps to catch and release the GM2 that sits on the shell of the bubbles. It can then be degrading together with the degradation enzyme Hex A to harmless GM3. However, when the function of Hex A is blocking; it is storing with fatal consequences for nerve cells.

Drugs that are currently on the market only partially fulfill this requirement. Perhaps gene replacement therapy, which has already been successful in animal models and will soon be used in patients, will be more successful, said the biochemist. With the help of ferries, genes with the correct blueprint for the GM2 degradation enzyme will be introduced into the nerve cells of the brain.