Abstract
The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders.
Highlights
Multiple sclerosis (MS) is the most common cause of chronic neurological disability in young adults.[1]
We employed an affinity proteomics approach to identify proteins related to MS by using antibodies on three different types of sample material: plasma, cerebrospinal fluid (CSF), and brain tissue
Antibodies targeting IRF8, IL7, SLC30A7, methyltransferase-like protein 14 (METTL14), and growth associated protein 43 (GAP43) were most indicative for disease state and progression and chosen for immunofluorescence analysis of post-mortem brain tissue sections from MS patients
Summary
Multiple sclerosis (MS) is the most common cause of chronic neurological disability in young adults.[1]. Current diagnosis of MS currently relies on a combination of several clinical investigations, such as magnetic resonance imaging of the brain and identification of oligoclonal IgG in cerebrospinal fluid (CSF).[5] additional indicators of disease are needed because interindividual variations in neuropathological features and clinical manifestations complicate both an early-stage diagnosis and prediction of disease progression.[6,7]. Proteins in CNS tissue potentially hold much of the sought-after information. As true for other neurological diseases, it is a challenge to access samples of brain tissue for discovery-driven approaches. To otherwise gain insights into disease-related mechanism and pathophysiology, disease-specific protein profiles can be searched for in systemic plasma or proximal CSF.[8−11] The current scarcity of so-far reported disease-specific proteins within MS12 may be due to several reasons such as the limited number of samples and the aforementioned disease heterogeneity
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