Abstract
Multiple Sclerosis (MuS) is a complex multifactorial neuropathology, resulting in heterogeneous clinical presentation. A very active MuS research field concerns the discovery of biomarkers helpful to make an early and definite diagnosis. The sphingomyelin pathway has emerged as a molecular mechanism involved in MuS, since high levels of ceramides in cerebrospinal fluid (CSF) were related to axonal damage and neuronal dysfunction. Ceramides are the hydrolysis products of sphingomyelins through a reaction catalyzed by a family of enzymes named sphingomyelinases, which were recently related to myelin repair in MuS. Here, using a lipidomic approach, we observed low levels of several sphingomyelins in CSF of MuS patients compared to other inflammatory and non-inflammatory, central or peripheral neurological diseases. Starting by this result, we investigated the sphingomyelinase activity in CSF, showing a significantly higher enzyme activity in MuS. In support of these results we found high number of total exosomes in CSF of MuS patients and a high number of acid sphingomyelinase-enriched exosomes correlated to enzymatic activity and to disease severity. These data are of diagnostic relevance and show, for the first time, high number of acid sphingomyelinase-enriched exosomes in MuS, opening a new window for therapeutic approaches/targets in the treatment of MuS.
Highlights
Multiple Sclerosis (MuS) is a highly complex CNS disease characterized by a multifactorial pathogenesis and a great heterogeneity in clinical presentation[1,2]
cerebrospinal fluid (CSF) lipids from 20 MuS patients and 17 OND patients were analyzed by our already reported method[22] focusing on the acquisition of phosphatidylcholines (PCs) and SMs profile. 421 signals of PCs and SMs species were obtained following the data processing described in method section, and their relative intensities were subjected to different explorative statistical approaches with the aim of highlighting specific altered lipid patterns in MuS
MuS is presumed to be an autoimmune disease directed against the lipid-rich myelin sheath
Summary
Multiple Sclerosis (MuS) is a highly complex CNS disease characterized by a multifactorial pathogenesis and a great heterogeneity in clinical presentation[1,2]. Sphingolipids include sphingomyelins (SMs), ceramides and sphingosines, involved in the same molecular cascade, in which one component emerges from the other by sequential enzymatic reactions[7]. Higher phospholipid and lower sphingolipid content were found in white and gray matter from MuS patients compared to controls[9], while sphingosine content is increased www.nature.com/scientificreports/. Ceramides are the hydrolysis product of SMs through a reaction catalyzed by sphingomyelinase (SMase), a family of enzymes that have recently become of interest in MuS. We applied a lipidomics approach for investigating CSF phospholipid profile, with particular focus on SMs, in patients with MuS compared with CSF from patients suffering from Other Central and Peripheral Neurological Disease (C_OND and P_OND, respectively). CSF exosomes carrying ASMase were identified, gated and counted in the enrolled patients
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