Disruption of a “transporter” protein called MCT1 (also SL16A1) leads to the degeneration of muscle-controlling nerve cells (motor neurons) in animal and cell culture models of amyotrophic lateral sclerosis (ALS), an MDA-supported team of researchers has reported.
In addition, the team found that MCT1 activity is reduced in people with ALS and in mouse models of the disease.
The findings suggest that MCT1-based transport is a key mechanism used by an important type of central nervous system support cell called oligodendroglia to provide nutrients to motor neurons — specifically to the long fibers called axons that carry signals to and from motor neurons in the brain and spinal cord.
"This is a new function for this principle brain cell, and we were surprised to find that this cell and its energy support pathway were significantly injured in ALS models and in patients," Jeffrey Rothstein, director of the Johns Hopkins Brain Science Institute and Packard Center, and the MDA/ALS Center at Johns Hopkins University in Baltimore, said in a press release.
The research team published its findings July 11, 2012, in Nature. MDA supported Youngjin Lee and Brett Morrison, also at Johns Hopkins, for their contribution to this work. See Oligodendroglia Metabolically Support Axons and Contribute to Neurodegeneration to read the abstract (readers can purchase the complete article or view it at no cost with a subscription).
Oligodendroglia-specific MCT1 support is key
In research mouse models, Rothstein’s team first demonstrated that MCT1 transport is a mechanism utilized almost exclusively by oligodendroglia in the brain and spinal cord.
Next, the researchers used two different methods — one genetic and one drug-based — to inhibit the activity of MCT1 in cell cultures derived from mouse spinal cord tissue. In both groups, approximately 33 percent of neurons were lost after three weeks. MCT1 inhibition in live mice led to significant motor neuron loss as well.
Finally, the team showed that a complete absence of MCT1 is embryonic lethal– that is, mice that don’t have any MCT1 don’t survive long enough to be born. Mice that produce only 50 percent of the normal amount of MCT1 mature normally, but by the age of 8 months develop axon damage to motor neurons in the brain and spinal cord that is similar to the damage observed in the SOD1 ALS research mouse model and in people with ALS.
Although some MCT1 is associated with other cell types, the team showed that oligodendroglia-specific MCT1 loss is crucial to axon survival — and by extension, survival of motor neurons.
To learn more about oligodendroglia, view the transcript (Oligodendroglia cells: An interview with Jeffrey Rothstein) from the July 11, 2012, interview with Jeffrey Rothstein.
Lack of lactate
MCT1 shuttles small sugar molecules related to energy production, including one called lactate, between oligodendroglia and axons. Rothstein’s team showed that the primary transporter of lactate is MCT1. The new findings suggest that axon damage and subsequent motor neuron degeneration occur when decreased MCT1 activity diminishes the amount of lactate made available to accommodate the cell’s high energy needs.
Recent studies have shown that oligodendroglia, or possibly the immature cells that develop into oligodendroglia, are damaged in the SOD1 mouse.
Rothstein’s group found a more than 50 percent reduction of MCT1 activity in tissue samples taken from people with ALS compared to samples taken from unaffected individuals, which supports a role for oligodendroglia-associated MCT1 in ALS.
Further experiments are needed to confirm the contribution of decreased MCT1 activity in ALS and to determine whether methods such as transplanting oligodendroglia, or genetically or pharmacologically increasing MCT1 activity, can lengthen survival time in ALS mouse models.
A clear understanding of the processes that go awry in ALS is crucial to scientists’ efforts to develop therapies for the disease. As part of its commitment to advancing ALS research, MDA hosted a Neuron Symposium in May 2012. Rothstein served as co-chair of the event, which brought together more than a dozen of the world’s top scientists to focus on the contribution of nervous system support cells — including oligodendroglia — in ALS.