Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis

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.

Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis

“…The cause of myelin blistering is unknown and is the subject of our current research. It is tempting to speculate that swelling of axon–myelin units may be causally related to recently documented disturbances in neural development and energy metabolism 33 …”

“…It is tempting to speculate that swelling of axon–myelin units may be causally related to recently documented disturbances in neural development and energy metabolism. 33 …”

Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers

“…During the preparation of this manuscript, some new studies were published (i.e., 2020 to February 2021) describing proteomic changes in samples from MS patients [ 292 , 293 , 294 ] and animal models [ 295 ]. Bottom-up studies using CSF samples from MS patients reported the upregulation of apolipoproteins, augurin, receptor-type tyrosine-protein phosphatase gamma, and trypsin-1 compared to controls.…”

“…This suggests a unique change in proteome profile when MS progresses with little or no inflammation in the secondary progressive form of MS [ 294 ]. Moreover, the changes in proteins involved with neural development (e.g., semaphoring-7A, neural cell adhesion molecules, transforming growth factor beta 1, follistatin-related protein 1, transferrin) were reported [ 292 ]. These changes are similar to those in the samples from MS patients and those diagnosed with clinically isolated syndrome.…”

“…These changes are similar to those in the samples from MS patients and those diagnosed with clinically isolated syndrome. These findings suggest that disruption of neural structures may represent an early stage of MS development [ 292 ]. Importantly, a bottom-up study was also performed on CSF samples from newly diagnosed female RRMS patients (with mild neurological disability and no long-term drug therapy) and revealed the differential regulation of 69 canonical proteins including immunoglobulin, apolipoprotein, and complement [ 293 ].…”