Differences in cerebrospinal fluid from multiple sclerosis patients can play a key role in stopping treatment progression.

The burden of disability for people with multiple sclerosis (MS) can vary greatly depending on whether it is a recurrent or relapsing disease, a period of clinical remission or a progressive form, when they have undergone continuous neurological deterioration without clinical remission. . Effective treatments exist for relapsing / relapsing multiple sclerosis, but treatment for progressive multiple sclerosis is more difficult. Now a new article published in the journal Brain Researchers from the Graduate Center's Advanced Scientific Research Center (CURA), CUNY and the Friedman Brain Institute of Mount Sinai School of Medicine Icahn have identified potential mechanisms to guide the development of therapies to effectively manage progressive MS.

Previous research had suggested that dysfunction of neuronal mitochondria – the subcellular organelles producing energy – occurred in the brains of MS patients with progressive clinical disability. However, the molecular mechanisms underlying this process have remained inaccessible.

"Since the brain is bathed by cerebrospinal fluid (CSF), we asked whether the treatment of neurons cultured with CSF in patients with MS with relapse / remitting or progressive course of the disease would have possibly different effects on neuronal mitochondrial function, "said study Patrizia Casaccia, senior researcher, Einstein biology professor at Graduate Center and founding director of CURC's Neuroscience Initiative. "We detected dramatic differences in the form of neuronal mitochondria and their ability to produce energy.Only exposure to CSF ​​from patients with progressive MS caused the fusion and elongation of neuronal mitochondria, preventing them from CSF-induced neurodegeneration in order to define therapeutic strategies. "

Methodology

CSF samples were collected from 15 patients with relapsing / remitting MS and 29 with progressive MS. These samples have been characterized in detail, both functionally and metabolically. Video recordings of neurons from live and cultured rats exposed to CSF ​​revealed significant differences. The researchers detected a characteristic elongation of mitochondria exposed to CSF ​​samples from patients with progressive MS. This characteristic response was not present in CSF-exposed mitochondria in patients with relapsing / remitting MS. The biochemical characterization of mitochondrial activity also revealed that elongated mitochondria were less functional and therefore less able to produce energy, which ultimately resulted in the disappearance of neurons.

The research team has been looking deeper to determine the presence in the CSF of patients with progressive MS that may be at the origin of these mitochondrial changes and eventually, a increase in energy demand. Previous research has shown that mitochondria expand in order to generate more energy for cells in case of increased energy demand or decreased available glucose. The lipid profile of the CSF samples established by the researchers revealed that ceramide levels were increased in the CSF of patients with progressive MS.

"When we exposed cultured neurons to ceramides, we caused the same changes caused by CSF exposure in patients with progressive MS." We then discovered that ceramides induced neuronal damage by acting on two cellular mechanisms, "said Maureen Wentling, research badociate at Casaccia Lab and the first author of the study. "On one side, ceramides have impaired the ability of neurons to produce energy by directly damaging mitochondria, and on the other hand, they have also forced neurons to absorb glucose more rapidly. to provide energy to the cell. "

The researchers were able to prevent the neurotoxic effect of CSF on cultured neurons by adding glucose. Supplementation is not a sustainable approach in the diseased brain, however, a different approach will ultimately be needed to develop therapies that improve mitochondrial function in patients with progressive MS.