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 of these types, the midbrain dopamine-producing neurons play an important role
in a number of diseases, such as Parkinson's disease.
Credit: Nature Reviews/Molecular Cell Biology
Fat Influences Decisions Taken by Brain Cells
Scientists at Karolinska Institutet in Sweden have identified two molecules that play an important role in the survival and production of nerve cells in the brain, including nerve cells that produce dopamine
The discovery, which is published in the journal Nature Chemical Biology, may be significant in the long term for the treatment of several diseases, such as Parkinson's disease.
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 of 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 production of new nerve cells could be initiated.
The scientists used mass spectrometry and systematic
experiments on zebrafish and mice to identify two
molecules that bind to and activate LXR.
These two molecules are (1) cholic acid a bile acid
and (2) 24,25-EC a derivate of cholesterol.
Cholic acid, influences the production and survival of
neurons in the "red nucleus," which is important for incoming signals from other parts of the brain.
24,25-EC influences the generation of new dopamine-producing nerve cells, 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
"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. Embargoed for publication until Sunday 23 December 2012 at 18:00 UK time / 19:00 CET / 13:00 US EST.
For more information, please contact:
Ernest Arenas, Professor of Stem Cell Neurobiology
Department of Medical Biochemistry and Biophysics
Tel: +46 70 245 6663
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Karolinska Institutet is one of the world's leading medical universities. It accounts for over 40 per cent of the medical academic research conducted in Sweden and offers the country's broadest range of education in medicine and health sciences. Since 1901 the Nobel Assembly at Karolinska Institutet has selected the Nobel laureates in Physiology or Medicine. More on ki.se/english
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