Cerebrospinal fluid difference key to progression-halting drugs

July 19, 2019
Researchers have identified potential mechanisms that may inform the development of therapies that effectively manage progressive MS.

Previous research suggested dysfunction of neuronal mitochondria occurs in the brains of MS patients with progressive clinical disability. However, the molecular mechanisms underlying this process remained elusive. The researchers detected dramatic differences in the shape of the neuronal mitochondria and their ability to produce energy. Only exposure to the cerebrospinal fluid from progressive MS patients caused neuronal mitochondria to fuse and elongate while rendering them unable to produce energy. They searched for potential mechanisms of CSF-induced neurodegeneration with the intent to define therapeutic strategies.

Researchers at the Advanced Science Research Center at The Graduate Center, CUNY, and Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai took CSF samples from 15 patients with relapsing-remitting MS and 29 with progressive MS. Researchers detected a characteristic elongation of mitochondria exposed to CSF samples from progressive MS patients. This characteristic response was not present in mitochondria exposed to CSF from patients with a relapsing-remitting MS. Biochemical characterization of mitochondrial activity further revealed that elongated mitochondria were less functional and therefore less capable of producing energy, which eventually resulted in neuronal demise.

The research team looked deeper to determine what was present in the CSF of progressive MS patients that could be causing these mitochondrial changes and, possibly, an increased energy demand. Previous research indicated that mitochondria elongate in an effort to generate more energy for cells when there is enhanced energetic demand or a decrease in available glucose. The researchers' lipid profiling of the CSF samples revealed that CSF from progressive MS patients had increased levels of ceramides – a family of waxy lipid molecules.

When researchers exposed cultured neurons to ceramides, they elicited the same changes caused by exposure to CSF from progressive MS patients, and they further discovered that ceramides induced neuronal damage by acting on two cellular mechanisms. On one end, ceramides impaired the ability of neurons to make energy by directly damaging the mitochondria. On the other end, they also forced neurons to more rapidly uptake glucose in an attempt to provide energy for the cell.

The researchers were able to prevent the neurotoxic effect of CSF on cultured neurons by supplementing glucose. Supplementation isn't a sustainable approach in the diseased brain, however, so a different approach will ultimately be needed for developing therapies that improve mitochondrial function in patients with progressive MS.

The paper was published in the journal Brain.

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