Scientists at Karolinska Institutet 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 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:
Authors:
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 och Ernest Arenas.
Brain endogenous liver X
receptor ligands selectively promote midbrain
neurogenesis
Nature Chemical Biology, Advance Online Publication
23 December 2012, doi: 10.1038/nchembio.1156
http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.1156.html
Karolinska
Institutet
(MDN)
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