A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis

Abstract

Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of ‘virtual hypoglycosis’ induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.

Retrospective unbiased plasma lipidomic of progressive multiple sclerosis patients-identifies lipids discriminating those with faster clinical deterioration

“…4 E). This finding supports previous studies on the importance of this lipid in neurodegeneration 9 . The remaining two hexosyl-ceramides [DiHexCer(d18:1/18:2), and DiHexCer(d18:1/18:3)] were less abundant in PPMS patients compared to controls (Fig.…”

“…4E). This finding supports previous studies on the importance of this lipid in neurodegeneration 9 . The remaining two hexosyl-ceramides 4F) and a positive correlation was found between its levels and MRI metrics of decreased CblWMV at the one-year follow-up.…”

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

“…Recent research has revealed important correlation of mitochondrial dynamics and the pathophysiology of brain diseases, as Alzheimer's. Disease (AD), Parkinson's Disease (PD) and Multiple Sclerosis (MS) (11)(12)(13). Disturbances in mitochondrial dynamics may influence many cellular and molecular pathways, as calcium-dependent immune activation, transcription factors phosphorylation, cytokine secretion, organelle transference and even cell death.…”

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

“…Cerebrospinal fluid (CSF) from MS patients significantly alters neuronal mitochondria shape and glucose uptake, coupled with a suppression of mitochondria complexes I, III, and IV, as well as reduced ATP production. The authors attribute this to CSF exosomes containing ceramides and the phosphorylation of dynamin-related protein (DRP)1 [43]. Such data link to previous studies showing suboptimal mitochondria functioning in MS and indicate an attempt to increase glycolysis under challenge [44].…”