The same scientists have previously shown that receptors known as ‘liver X receptors’ or LXR, are necessary for the production of different types of nerve cells, or neurons, in the developing ventral midbrain. One these types, the midbrain dopamine-producing neurons play an important role in a number of diseases, such as Parkinson’s disease.
What was not known, however, was which molecules stimulate LXR in the midbrain, such that the production of new nerve cells could be initiated. The scientists have used mass spectrometry and systematic experiments on zebrafish and mice to identify two molecules that bind to LXR and activate it. These two molecules are named cholic acid and 24,25-EC, and are bile acid and a derivate of cholesterol, respectively. The first molecule, cholic acid, influences the production and survival of neurons in what is known as the ‘red nucleus’, which is important for incoming signals from other parts of the brain. The other molecule, 24,25-EC, influences the generation of new dopamine-producing nerve cells, which are important in controlling movement.
One important conclusion of the study is that 24,25-EC can be used to turn stem cells into midbrain dopamine-producing neurons, the cell type that dies in Parkinson’s disease. This finding opens the possibility of using cholesterol derivates in future regenerative medicine, since new dopamine-producing cells created in the laboratory could be used for transplantation to patients with Parkinson’s disease.
“We are familiar with the idea of cholesterol as a fuel for cells, and we know that it is harmful for humans to consume too much cholesterol”, says Ernest Arenas, Professor of Stem Cell Neurobiology at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, who led the study. “What we have shown now is that cholesterol has several functions, and that it is involved in extremely important decisions for neurons. Derivatives of cholesterol control the production of new neurons in the developing brain. When such a decision has been taken, cholesterol aids in the construction of these new cells, and in their survival. Thus cholesterol is extremely important for the body, and in particular for the development and function of the brain.”
The study has been financed by grants from (among other bodies) the Swedish Brain Foundation, the European Union, the Swedish Foundation for Strategic Research, Karolinska Institutet and the Swedish Research Council.
Publication: ‘Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis’, Spyridon Theofilopoulos, Yuqin Wang, Satish Srinivas Kitambi, Paola Sacchetti, Kyle M Sousa, Karl Bodin, Jayne Kirk, Carmen Saltó, Magnus Gustafsson, Enrique M Toledo, Kersti Karu, Jan-Åke Gustafsson, Knut R Steffensen, Patrik Ernfors, Jan Sjövall, William J Griffiths, and Ernest Arenas, Nature Chemical Biology, Advance Online Publication 23 December 2012, doi: 10.1038/nchembio.1156.