snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses.

Area of Science:

• Neuroimmunology
• Genomics
• Translational Medicine

Background:

• Clinical and genetic heterogeneity in progressive multiple sclerosis (MS) complicates therapeutic development.
• A deeper understanding of cellular and molecular underpinnings is crucial for advancing MS treatments.

Purpose of the Study:

• To investigate inter- and intra-donor heterogeneity in gene expression within MS brain tissue.
• To identify cellular and molecular differences contributing to MS pathology and patient stratification.

Main Methods:

• Analysis of 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples (MS and control donors).
• Examination of cell type-specific gene expression changes in gray and white matter.
• Stratification of patients based on gene expression variability to identify distinct pathological processes.

Main Results:

• Distinct cell type-specific gene expression alterations were observed between MS gray and white matter.
• MS lesion subtypes showed varied cellular compositions but conserved cell-type gene expression patterns.
• Patient-specific effects explained the majority of gene expression variability, enabling patient stratification.

Conclusions:

• Molecular profiles reveal significant patient heterogeneity in multiple sclerosis pathology.
• Stratifying MS patients based on molecular data can illuminate distinct pathological processes.
• Integrating brain, blood, and CSF molecular data holds promise for precision medicine in MS.