When we hear the word cholesterol we often have very negative thoughts of clogged arteries, heart attacks and strokes. However, cholesterol serves several vital roles in our bodies. It regulates the fluidity of the membranes of our cells, serves as a precursor for the synthesis of steroid hormones (such as estrogen, testosterone, cortisol and others), and is an important signaling molecule for several biological processes. Therefore. cholesterol is not all bad. Cholesterol when we get too much of it and our bodies handle the excess cholesterol poorly. Then wandering cells called macrophages have to mop up the excess cholesterol, but it makes them sick, and they get lost underneath the inner layers of blood vessels. That, however, is for another blog post.
In the present study, scientist from Karolinska Institutet in Sweden have identified two molecules, both of which are derivatives of cholesterol, that can help turn brain cells into the kind of cells that die during Parkinson’s disease. This finding might be useful for producing large quantities of neurons in the laboratory for therapeutic purposes.
As I have blogged before Parkinson’s disease results from the death of midbrain neurons that use the neurotransmitter dopamine. Because these midbrain neurons project to, in part, regions of the brain involved in voluntary movement, the death of the dopamine-using neurons in the midbain produces pronounced defects in voluntary movement and resting stability. Several experiment in humans and laboratory animals have definitively shown that cell transplantation experiments can improve the symptoms of patients with Parkinson’s disease. Therefore, cultivating and growing dopamine-using neurons in the laboratory is of cardinal importance in the treatment of this devastating disease.
Workers in the laboratory of Ernest Arenas investigated molecules known to play a role in the differentiation of midbrain neurons. They discovered that a group of receptors collectively known as “liver X receptors” or LXRs are necessary for making ventral midbrain neurons from neural stem cells. However, they were unsure what molecules bound to the LXRs in order to activate them.
Enter cholesterol stage right. By subjecting LXRs to a cocktail of molecules from living organisms and analyzing by means of mass spectrometry, they discovered that two molecules, cholic acid (a bile salt), and 24,25-EC, both of which are derivatives of cholesterol, bind to LXR and activate it.
Cholic acid binds to LXR and stimulates the neural stem cells to form a group of midbrain cells known as the “red nucleus.” The red nucleus receives signals from several different parts of the brain to coordinate the movements of several different parts of the body. The other molecule, 24,25-EC binds to LXR and induces the formation of dopamine-using midbrain neurons – the ones that die off during Parkinson’s disease.
These data could open the possibility that cholesterol derivatives can be used to produce dopamine-using neurons from neural stem cells to treat Parkinson’s disease.
Ernest Arenas, professor of stem cell neurobiology in the department of biochemistry and biophysics, who led this study said: “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. 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.”