Uncovering the Proteins Behind Multiple Sclerosis: How a Multi-Omics Breakthrough Reveals New Clues in the Blood and Brain
Multiple sclerosis (MS) is a complex immune-mediated disease in which the immune system attacks the central nervous system, leading to inflammation, demyelination, and eventual neurodegeneration. Although genetics clearly contributes to MS susceptibility, the biological processes linking genetic variation to disease activity are not fully understood. A new integrative study sheds light on this gap by combining genetics, proteomics, transcriptomics, and long-term clinical data to identify protein biomarkers that may influence both MS onset and progression. The result is one of the most comprehensive protein-level maps of MS risk to date.
Why Proteins Matter in Understanding MS
Proteins act as functional outputs of genetic information, making them ideal candidates for understanding disease mechanisms and therapeutic targeting. Genome-wide association studies (GWAS) have identified hundreds of MS-associated genetic variants, yet most lie outside protein-coding regions. That makes it difficult to determine which biological pathways are disrupted. Protein quantitative trait loci (pQTLs), which link genetic variants to protein abundance, provide a missing bridge between DNA and disease biology. By examining plasma proteins and brain proteins separately, the study aimed to uncover which genetically regulated proteins truly influence MS susceptibility.
A Multi-Layered, Multi-Omics Strategy
To capture a full picture, the researchers integrated MS GWAS data from over 14,000 cases with large-scale proteomics datasets from blood and post-mortem brain tissue. They then layered tissue-level gene expression data and single-cell transcriptomics from immune and neural cells. Finally, they evaluated how genes corresponding to these proteins predicted long-term disability worsening in a 15-year MS cohort. This approach allowed the researchers not only to identify protein signals, but to confirm whether these signals aligned with transcriptional changes in specific immune or brain cell populations and whether they predicted real-world clinical outcomes.
Five Plasma Proteins Newly Linked to MS Risk
The study identified five plasma proteins—FCRL3, MAPK3, IDUA, FLRT3, and TAPBPL—whose genetically predicted abundance was significantly associated with MS susceptibility after multiple-testing correction. Some proteins, such as FCRL3 and MAPK3, showed inverse associations, meaning lower protein levels were linked to higher MS risk. Others, such as FLRT3 and TAPBPL, showed positive associations, indicating that higher abundance increased MS risk. Of particular interest was TAPBPL, which plays a key role in peptide loading for antigen presentation. In immune-cell data, TAPBPL expression was consistently elevated in MS, especially in B cells, CD8+ T cells, and natural killer cells, reflecting its potential role in shaping pathogenic immune activation.
Thirty-Four Brain Proteins Associated with MS Susceptibility
Beyond plasma, the investigators uncovered 34 brain proteins genetically linked to MS risk in the discovery dataset. Eighteen of these replicated in an independent brain cohort. Among them, TSFM showed the strongest association, with compelling evidence that its genetic signal colocalized with MS GWAS loci. TSFM is a mitochondrial elongation factor involved in protein synthesis within mitochondria, highlighting a possible link between mitochondrial dysfunction and MS pathogenesis. Other notable proteins included FKBP2, which showed reduced abundance in MS and was strongly downregulated in mature oligodendrocytes, and ZC2HC1A, previously linked to conversion from clinically isolated syndrome to MS. Several proteins demonstrated consistent expression alterations in neurons or oligodendrocyte lineage cells, emphasizing cell-type–specific vulnerabilities.
Cell-Specific Expression Reveals Vulnerable Immune and Neural Populations
The integration of single-cell and single-nucleus RNA-seq provided deeper insight into how these protein associations manifest at the cellular level. TAPBPL and MAPK3 showed expression patterns in immune cells that mirrored their plasma-based risk effects. In brain tissue, multiple proteins exhibited differential expression across neuronal subtypes and oligodendrocyte clusters. For instance, FKBP2, AUH, PRICKLE1, TMEM160, and WBP2 displayed consistent changes in specific oligodendrocyte or neuronal clusters that aligned with their direction of protein-level associations with MS risk. This reinforces the concept that MS pathogenesis involves not only immune dysregulation but also intrinsic vulnerabilities within the brain’s glial and neuronal networks.
Proteins That Influence Both MS Risk and Long-Term Disability
Importantly, the study extended its findings into clinical prognosis. Of the 39 candidate proteins linked to MS susceptibility, 23 had corresponding genes associated with disability worsening in the 15-year longitudinal AusLong cohort. This means many of the same proteins that predispose individuals to MS may also drive disease progression. Genes corresponding to IDUA, FLRT3, MAPK3, and several brain-derived proteins displayed significant associations with worsening Expanded Disability Status Scale (EDSS) trajectories. These results suggest that the biological processes influencing MS onset may continue to modulate neurodegeneration and functional decline over time.
Therapeutic Opportunities: Protein Targets Already Linked to Existing Drugs
Using a drug–gene interaction database, the authors identified existing compounds that interact with some of the candidate proteins. The most well-established was vitamin B12, which interacts with MTHFR, a protein whose increased brain abundance was associated with higher MS risk. Other compounds included ravoxertinib, which targets MAPK3, and BIIB021, which targets CARM1. While most interactions require further validation, this protein-centered map provides an informed starting point for drug repurposing and new therapeutic development.
Strengths and Limitations of the Study
The study’s strengths include its integration of large proteomic datasets with GWAS and its validation across multiple tissue types, cell types, and clinical outcomes. However, there were unavoidable limitations. Brain proteomic datasets had relatively small sample sizes, reducing replication power. Single-cell analyses were limited by the rarity of high-quality MS brain tissue. The study also could not evaluate the HLA region of chromosome 6 due to complex linkage disequilibrium patterns. Nevertheless, these constraints do not diminish the value of the findings; instead, they point to opportunities for future work using larger and more diverse multi-omics datasets.
A Foundation for MS Biomarker Discovery
This landmark study identifies a set of plasma and brain proteins that not only correlate with MS genetic risk but also display consistent transcriptional patterns in relevant immune and brain cell types. Many of these proteins are also linked to long-term disability worsening. Together, these insights provide a powerful foundation for understanding MS pathobiology at the protein level and for developing targeted biomarkers and therapeutics. As the field moves toward personalized medicine, protein-based signatures may help identify individuals at higher risk, inform treatment decisions, and offer new avenues for intervention—shifting MS management from reactive to proactive strategies.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Lin, X., Yang, Y., Gresle, M., Cuellar-Partida, G., Han, X., Stankovich, J., ... & Zhou, Y. (2023). Novel plasma and brain proteins that are implicated in multiple sclerosis. Brain, 146(6), 2464-2475.
