Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you tell us a little bit about oligodendroglia cells? What were they were previously thought to do and what have you now discovered that they do?
There are three principle cells in the brain: neurons and two types of glial cells. One type is called an astrocyte. These were well known to inactivate neurotransmitters like glutamate, and provide metabolic support to neurons.
The other type of glial cell is oligodendroglia, or ‘oligos’. Their role was generally thought to be supportive of the conduction of the actual axon impulse. They wrap around long nerves called axons in the brain and insulate them and allow fast communications between neurons.
These cells were also theorized to provide some kind of metabolic support, but there really had been no proof of that in animals.
What we discovered, which is not what we set out to discover, is that ‘oligos’ are a major metabolic supporters of the long axons.
When your brain communicates down to your spinal cord, there can be 2-3 feet long axons. The cells involved obviously need energy to support the flow of information.
It was originally thought that astrocytes provided energy to these long axon cells; but, in fact, at least one element of it turns out to be an oligodendroglial function.
This is very exciting, as these cells have been studied for 120-140 years and it was not previously known that they had this function.
How did your research originate?
In reality, we were trying to study this property in astrocytes, because our collaborator on the paper, Pierre Magistretti from Switzerland, had long theorized that astrocytes provide energy in the form of lactate.
In the body, most of our energy comes from glucose; however, lactate is a less efficient but clear energy supporter of cells. Pierre theorized that this occurs in astrocytes in the brain.
We were studying astrocyte abnormalities in a disease called amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease in the United States. In ALS- the large neurons that control muscle, called motor neurons, go on to slowly degenerate. Their death leads to respiratory- breathing- failure- and death. It that disease, astrocytes were known to be affected – and the injury to astrocytes we had discovered years ago, was a significant contributor to the death of motor neurons.
We were now beginning to look at the lactate shuttle and wondering whether it might be abnormal. So, we sought out what we thought would be an astrocyte pathway. We used molecular reporter mice and were shocked to learn that in animals, this pathway actually occurred in ‘oligos’ and not in astrocytes.
The previous literature had largely been in cultured cells. This shows the problem that sometimes occurs when you study cultured cells rather than whole animals.
We then needed to discover whether this transporter pathway, involving a protein called MCT1, was found only in ‘oligos’ or whether it predominantly in ‘oligos’. We also wanted to discover how it was affected by disease. To answer this question we had to develop mice that were lacking the transporter involved.
Ultimately, we found that the process, that is, the metabolic supply of lactate from oligos to neurons is in fact essential, and without it animals can develop neurodegenerative diseases—and by inference- so could people.
It was recently described in the news that this discovery could be important in treating neurodegenerative diseases such as ALS and multiple sclerosis. Please could you tell us a little bit about how these diseases attack the body?
These diseases affect the body in many different ways. Alzheimer’s, Huntington’s disease and ALS all have multiple different ways that they can lead to degenerative neurons.
There is no one central pathway in any neurodegenerative disease. All the diseases are multifactorial.
Our research shows that these cells, oligodendroglia, play a significant role in degenerative diseases. This is new as we never thought that they played this role before.
Are there any particular neurodegenerative diseases that you think will benefit more from this discovery than others?
I think you have to be careful when proposing that there will be specific benefits of this discovery. It is quite early—but the pathway certainly has therapeutic potential. I do, however, think it is worth experimenting further into the link between this pathway in ‘oligos’ and Multiple Sclerosis (MS) in particular.
The literature has already shown that these ‘oligo’ cells become injured in MS. Our data might suggest, although we didn’t prove it, that MS may be caused by an injury to this pathway involving the lactate shuttle.
How could your discovery help treat such neurodegenerative diseases?
I can only really speak for ALS. There is an evolving literature that these cells (‘oligos’) become injured in ALS. Our data suggests that they lose this function. We don’t yet know how they become injured or lose this function in ALS, but my colleagues at Johns Hopkins and my lab are aggressively studying that.
One possibility, that we did not explore in the paper but we are now doing, is what if we make more of the protein involved in the pathway? Would this have a protective effect? This is the next phase of our research.
We are well-engaged in studies now to find small drugs that will activate the lactate transporter and make it more efficient. We have found a few candidate drugs already, but it is very early stages, so they are not ready for trials in patients yet.
What do you think the future holds for the treatment of neurodegenerative diseases?
There are a couple of ways of answering this.
One is to identify the pathways that in some way lead to neural injury. Every such pathway then becomes a candidate therapeutic pathway.
The issue with degenerative diseases is that they are lengthy – they span 1-10 years or more. Some pathways are very active early in the disease; therefore you might want to intervene early. Some pathways are active later in the disease.
Understanding this temporal relationship is critical. The sequential molecular basis of the disease will determine how and when you treat it.
For example, if there was data showing that ‘oligos’ play a part in ALS very early on in the disease. Then we would like to intervene very early on in the pathway.
The second way of answering the question is to focus on genetics. For example, there are several genes involved in ALS.
One way of providing treatment for the disease, is to turn the gene off. There is research going into this right now.
Do you have any plans for further research into this field?
We are trying to understand:
- why oligodendroglia are damaged
- where the relevant protein is localised
- how the protein is regulated, i.e. how the gene for it is it turned on and off
Where can readers find more information?
They can find more information at:
About Jeffrey Rothstein
Jeffrey D. Rothstein, M.D., Ph.D. is the John W. Griffin Director for the Brain Science Institute, as well as a Professor of Neurology and Neuroscience, and the Founding Director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine.
In 1977, he received his undergraduate degree in Neuroscience from Colgate University, followed by his Master’s degree in Neurochemistry-Biopsychology from the University of Chicago in 1979. Dr. Rothstein continued his graduate education at the University of Illinois College of Medicine and Health Sciences Center to receive his Doctorate in Physiology and Biophysics-Neurochemistry in 1984, as well as his Medical degree in 1985.
His clinical training included an internship at the University of North Carolina Memorial Hospital, followed by his Neurology Residency at Johns Hopkins Hospital. After completing his residency in 1989, he continued his medical education at Johns Hopkins through a Neuromuscular Fellowship.
In 1991, Dr. Rothstein accepted a position as Assistant Professor in the Department of Neurology at Johns Hopkins University, which he held until 1994 when he was promoted to Associate Professor of Neurology, with additional appointments in the Graduate Training Program in Cellular and Molecular Medicine, as well as the Department of Neuroscience.
In 2000, in addition to being promoted to his current position as Professor of Neurology and Neuroscience, Dr. Rothstein became the Director and Founder of the Robert Packard Center for ALS Research, which has uses philanthropic dollars to support the most promising researchers around the world to work collaboratively to develop models of ALS and to ALS therapies.
In 2011, he also accepted his current position as Director of the Johns Hopkins Brain Science Institute (BSi). A respected and internationally renowned neuroscientist, Dr. Rothstein is credited as being one of the world’s top ALS researchers and has over 25 years as a clinician scientist studying ALS pathophysiology, astrocyte biology and therapy discovery; it was his research on ALS pathogenesis that lead to the first successful, FDA-approved drug to alter neurodegeneration in ALS.
In addition to running a basic science lab and an ALS clinic at Johns Hopkins which evaluates and manages over 350 ALS patients every year, the BSi also runs a drug discovery group consisting of 25 medicinal chemists to identify novel therapeutics for neurological and psychiatric disease.