Novel plasma and brain proteins that are implicated in multiple sclerosis.

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Multiple sclerosis (MS) susceptibility is influenced by protein variations in plasma and brain.
• Understanding these proteomic changes is crucial for drug repurposing and therapeutic strategies.
• The role of genetically predicted protein abundance in MS pathogenesis is not well understood.

Purpose of the Study:

• To identify novel proteins associated with multiple sclerosis susceptibility.
• To investigate the tissue-level and cell-level gene expression patterns of candidate proteins.
• To explore the association of candidate genes with MS disability worsening.

Main Methods:

• Integrated plasma and brain proteomics with genome-wide association studies for MS.
• Utilized summary-based methods to identify candidate proteins.
• Examined gene expression quantitative trait data in whole-blood and brain tissues.
• Performed cell-specific gene expression analysis in immune and brain cells.
• Assessed gene associations with disability worsening in a longitudinal MS cohort.

Main Results:

• Identified 39 novel proteins associated with multiple sclerosis risk.
• Found consistent associations for four plasma protein-related genes in whole-blood.
• Observed TAPBPL upregulation in multiple sclerosis immune cells (B cells, CD8+ T cells, NK cells).
• Replicated 18 out of 34 candidate brain proteins and found 14 associated genes in brain tissue.
• Discovered differential gene expression in neuron and oligodendrocyte clusters for six brain candidates.
• Associated 23 protein-coding genes with disability worsening in MS patients.

Conclusions:

• The study presents a set of novel protein biomarkers for multiple sclerosis.
• Findings are supported by concordant transcriptomic data at tissue and cell levels.
• Highlights heterogeneity in cell-specific transcriptional profiles and links candidates to disease progression.
• Provides an anchor for future research into MS mechanisms and therapeutic development.