Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics

Abstract

Axonal damage is a prominent cause of disability and yet its pathogenesis is incompletely understood. Using a xenogeneic system, here we define the bioenergetic changes induced in rat neurons by exposure to cerebrospinal fluid samples from patients with multiple sclerosis compared to control subjects. A first discovery cohort of cerebrospinal fluid from 13 patients with multiple sclerosis and 10 control subjects showed that acute exposure to cerebrospinal fluid from patients with multiple sclerosis induced oxidative stress and decreased expression of neuroprotective genes, while increasing expression of genes involved in lipid signalling and in the response to oxidative stress. Protracted exposure of neurons to stress led to neurotoxicity and bioenergetics failure after cerebrospinal fluid exposure and positively correlated with the levels of neurofilament light chain. These findings were validated using a second independent cohort of cerebrospinal fluid samples (eight patients with multiple sclerosis and eight control subjects), collected at a different centre. The toxic effect of cerebrospinal fluid on neurons was not attributable to differences in IgG content, glucose, lactate or glutamate levels or differences in cytokine levels. A lipidomic profiling approach led to the identification of increased levels of ceramide C16:0 and C24:0 in the cerebrospinal fluid from patients with multiple sclerosis. Exposure of cultured neurons to micelles composed of these ceramide species was sufficient to recapitulate the bioenergetic dysfunction and oxidative damage induced by exposure to cerebrospinal fluid from patients with multiple sclerosis. Therefore, our data suggest that C16:0 and C24:0 ceramides are enriched in the cerebrospinal fluid of patients with multiple sclerosis and are sufficient to induce neuronal mitochondrial dysfunction and axonal damage.

Relationship of grey and white matter abnormalities with distance from the surface of the brain in multiple sclerosis

“…A CSF-mediated factor perhaps offers a more straightforward explanation, being in close proximity to both the inner and outer brain surfaces. However, while there is in vitro evidence that CSF from people with MS is both myelotoxic and neurotoxic,27 28 this has not been shown in vivo . Meningeal inflammation has been implicated in the pathogenesis of cortical GM lesions, and lesional and extralesional neuronal loss,11 12 but ependymal changes in MS do not appear to be closely linked with underlying WM lesion formation1 and, to the best of our knowledge, no studies have looked for associations between ependymal abnormalities and axonal pathology in WM.…”

Cytokine-induced release of ceramide-enriched exosomes as a mediator of cell death signaling in an oligodendroglioma cell line

“…We envision that shedding of Cers may promote the autoimmune response that occurs under demyelinating conditions in the central nervous system. There is evidence for an accumulation of Cer species, including C16:0-, C18:0-, C18:1-, C24:0-, and C24:1-Cer, in multiple sclerosis plaques and/or animal models of the disease (44,45,51), as well as increased levels of C16:0-and C24:0-Cer in the multiple sclerosis cerebrospinal fluid (52). However, with respect to such in vivo significance of our present findings, it would be important to first verify the phenomenon of exosome-mediated cell death signaling in primary oligodendrocytes prior to its in vivo validation.…”

Interferon-Beta Increases Plasma Ceramides of Specific Chain Length in Multiple Sclerosis Patients, Unlike Fingolimod or Natalizumab

“…C 18:0 ceramide accumulates in human MS lesions, while C 16:0 , C 18:0 , and C 20:0 ceramides were found in lesions in a cuprizone animal model of demyelination (Kim et al, 2012). On contact with neurons, the CSF of MS patients induces bioenergetic dysfunction and oxidative damage, due to increased C 16:0 and C 24:0 ceramides (Vidaurre et al, 2014). The major cellular source of ceramides in MS is reactive astrocytes, which show enhanced expression of enzymes involved in sphingolipid metabolism (van Doorn et al, 2012).…”