Abstract
Despite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.
Highlights
Despite intensive research, the aetiology of multiple sclerosis (MS) remains unknown
They argue that models that consider inflammation as secondary are supported by several observations in MS brains including lesions with apoptotic oligodendrocytes without inflammatory c ells[9], abnormal lipid biochemistry in otherwise normal appearing brain tissues[10], global alterations revealed by advanced spectroscopic methodologies before they become visible by commonly applied methods such as histochemical staining and conventional magnetic resonance imaging[11,12,13], and epigenetic changes in pathology-free regions of multiple sclerosis–affected brains that influence oligodendrocyte susceptibility to damage[14]
In previous work on cohort 1, explorative multivariate analysis of the cerebrospinal fluid (CSF) proteome separated the individuals into two groups with MS patients and controls present in both groups: One group but not the other had significantly increased levels of CSF IgG indicative of inflammation[16]
Summary
The aetiology of multiple sclerosis (MS) remains unknown. Stys and co-workers hypothesized that MS is a disease initiated within the CNS by degeneration of the inner myelin sheath, which secondarily triggers inflammation[6,7,8] They argue that models that consider inflammation as secondary are supported by several observations in MS brains including lesions with apoptotic oligodendrocytes without inflammatory c ells[9], abnormal lipid biochemistry in otherwise normal appearing brain tissues[10], global alterations revealed by advanced spectroscopic methodologies before they become visible by commonly applied methods such as histochemical staining and conventional magnetic resonance imaging[11,12,13], and epigenetic changes in pathology-free regions of multiple sclerosis–affected brains that influence oligodendrocyte susceptibility to damage[14]. The aim of the present publication was to search for molecular signatures of MS within the CSF proteome pattern while considering the heterogeneity of the disease
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