Gaucher disease and the Sphinx

Sphingosine, a compound as enigmatic as the sphinx, plays a key role in the metabolic disorder Gaucher disease. Scientists from the Bonn research center caesar have identified some of the complex molecular mechanisms of how the disease develops. These findings were published in the Journal of Biological Chemistry (JBC) and could contribute to the development of new therapies in the future.

Bonn 31 March 2017. Gaucher disease is a genetic disorder of lipid metabolism. There are very different manifestations of the disease: some patients suffer from serious neurological disorders and often die in childhood. Other patients are particularly affected by organ enlargement, especially the liver and spleen. The symptoms can be mitigated by medication. Today, it is known that a mutation in a particular gene, the so-called GBA1, is responsible for the disease. However, it is puzzling why one and the same mutation causes such different symptoms and clinical pictures.

Scientists from the research group "Molecular Physiology", headed by Dr. Dagmar Wachten, have looked more closely at the metabolic processes. The gene sequence GBA1 is responsible for the production of the enzyme GBA1, which plays an important role in the degradation of complex lipid-sugar compounds. Such lipid-sugar compounds, also referred to as glycosphingolipids, are building blocks of cell membranes. In the cell, old membrane building blocks are permanently removed and replaced by new ones. This is achieved by the lysosomes, cell organelles, which fulfill the tasks of a waste recycling plant in human and animal cells. In the lysosomes, the enzyme GBA1 becomes active and degrades the glycosphingolipids into smaller fragments.

In patients suffering from Gaucher disease, the enzyme GBA1 does not function properly. As a result, the lysosomes swell and finally overflow like a garbage can: lipid-sugar compounds spill out of the lysosomes and swim around in the cell. Now a first emergency plan comes into force: The enzyme GBA2 takes over and splits the lipid-sugar compounds outside the lysosomes. In this degradation process, inter alia, sphingosine is produced. Sphingosine was discovered over a hundred years ago by a German researcher, who named the enigmatic substance in reference to an Egyptian sphinx. Unfortunately, sphingosine is toxic to the cells. To prevent the poisoning of the cell, a second emergency plan regulates the activity of the enzyme GBA2.

To unravel this regulatory mechanism of the cell and to visualize the activity of the enzyme GBA2, the scientists have applied a trick. The sugar-lipid compound to be degraded was replaced by an analogous compound, whose degradation produces a fluorescent product. Measuring this fluorescence thus makes the activity of the enzyme visible. In this way, the researchers could show that the activity of the enzyme GBA2 is inhibited by sphingosine. Experiments in living organisms and in the test tube always produced the same results: The higher the sphingosine concentration in the cell, the less active is GBA2. The researchers also discovered the mechanism behind this. Sphingosine binds to GBA2 and thus reduces the activity of the enzyme. This effect is reversible - as soon as the sphingosine concentration decreases, the enzyme GBA2 returns to its old form.

The regulatory mechanisms decrypted by the caesar scientists could in the future help to develop new therapies for Gaucher disease patients. However, there are still questions open: Why do the same genetic defects and biochemical findings cause such different clinical pictures? What is the effect of the enzyme GBA2 on the growth and function of nerve cells? Is there a link between the activity of GBA2 and the neurological disorders that may be associated with Gaucher disease? Is there a way to intervene in the degradation of lipid-sugar compounds in the cell in a way that toxic degradation products, such as sphingosine, do no harm? Sphingosine, the substance resembling a sphinx, thus continues to mystify.

Original publication
Schonauer S., Körschen H.G., Penno A., Rennhack A., Breiden B., Sandhoff K., Gutbrod K., Dörmann P., Raju D.N., Haberkant P., Gerl M.J., Brügger B., Zigdon H., Vardi A., Futerman A.H., Thiele C., Wachten D. (2017) “Identification of a feedback loop involving beta-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease” J Biol Chem. 2017
DOI: 10.1074/jbc.M116.762831

Contact
Dr. Dagmar Wachten
Minerva Max Planck Research Group "Molecular Physiology"
Member of the Bonn Cluster of Excellence "ImmunoSensation"
Phone: +49(0)228/9656-311
E-mail: dagmar.wachten@caesar.de

caesar foundation
The caesar foundation is associated with the Max Planck Society and operates a center for neuroscience research in Bonn. The scientific work is carried out according to the excellence criteria of the Max Planck Society.