Multiple sclerosis (MS) is an often-disabling disease of the central nervous system caused by damage to the myelin coating around the nerves.
Multiple sclerosis (MS) is an often-disabling disease of the central nervous system caused by damage to the myelin coating around the nerves. The disease is quite variable, but falls into two broad types, relapsing-remitting MS (RRMS), in which patients often go into clinical remission, and progression MS, which does not have remission periods, but is marked by continued deterioration. RRMS affects about 85% of MS patients, although about half of RRMS patients eventually develop progressive disease.
Researchers with City University of New York and the Icahn School of Medicine at Mount Sinai have identified specific biological differences between the two types of diseases, which has the potential to lead to new therapeutic approaches and diagnostic testing. They published their research in BRAIN, A Journal of Neurology.
“Because the brain is bathed by the CSF [cerebral spinal fluid], we asked whether treating cultured neurons with the CSF from MS patients with a relapsing/remitting or a progressive disease course would possibly elicit different effects on neuronal mitochondrial function,” Patricia Casaccia, professor of biology at City University and Mount Sinai, told Genetic Engineering & Biotechnology News. “We detected dramatic differences in the shape of the neuronal mitochondria and their ability to produce energy.”
Earlier research has suggested that mitochondrial dysfunction in nerve cells might be the key to progressive MS, but molecular mechanisms that cause it were unknown. Casaccia and her team took the CSF from RRMS patients and progressive MS patients. They then exposed live-cultured rat neurons to different CSF. They took time-lapse videos and utilized a mitochondrial tracer to allow imaging and visualization of the mitochondria.
There were very different effects between the samples.
“Notably, we detected a substantial elongation of these organelles, coalescing to form a tubular network only in neuronal cultures exposed to the CSF from progressive patients,” the researchers wrote.
This was not observed in the mitochondria bathed in CSF from RRMS patients. More tests found that the elongated mitochondria not only were shaped differently but didn’t produce as much energy or function as normal mitochondria or those exposed to CSF from RRMS patients.
Earlier research has suggested that mitochondria change their shape to try to create more energy when there is increased energy demands or a diminished source of glucose. The researchers heated up the samples to destroy any proteins, then re-tested them. This eliminated the possibility of proteins being responsible for the effects. They found that the mitochondrial elongation still continued in the progressive MS samples.
They then analyzed the lipids in the CSF from both groups and identified increased levels of ceramides, especially ceramide C24, in the progressive MS CSF. Ceramides have previously been linked to MS. In fact, exposing rate neurons to ceramides causes the same mitochondrial elongation seen in progressive MS CSF.
They continued with the work, testing the ceramide-exposed neurons in low and high concentrations of glucose, finding that the presence of ceramides interferes with “the activity of respiratory chain complexes which become dysfunctional,” the researchers wrote.
In short, the neuron tries to compensate for the energy deficit by upregulating glucose transporters and in an attempt to meet the energy demand, redirects the energetic response towards glycolysis. This is inefficient and leads to neurotoxicity.
They also identified the two cellular mechanisms that ceramides cause damage to neurons.
“On one end, ceramides impaired the ability of neurons to make energy by directly damaging the mitochondria,” said Maureen Wentling, a research associate in Casaccia’s laboratory and the first author of the study. “On the other end, they also forced neurons to more rapidly uptake glucose in an attempt to provide energy for the cell.”
The researchers believe the new understanding of the mechanisms of mitochondrial damage in the two forms of MS may lead to new approaches to protecting mitochondria in progressive MS patients, while the ceramides may be biomarkers for diagnosing and following the progress of the disease.
