Identification of early neurodegenerative pathways in progressive multiple sclerosis

• Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease. 

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Keyword

proteome

transcriptome

animal experiment

animal model

antiinflammatory activity

Article

brain tissue

cell communication

cell interaction

central nervous system disease

cohort analysis

controlled study

degenerative disease

deterioration

disease course

disease model

drug targeting

female

gene knockdown

human

human tissue

in vivo study

male

microenvironment

mouse

multiple sclerosis

nerve cell

nerve degeneration

nonhuman

pathogenesis

protein interaction

proteomics

spatial analysis

transcriptomics

complication

disease exacerbation

metabolism

pathology

Central Nervous System Diseases

Disease Progression

Humans

Neurons

Publication and Content Type

ref (subject category)

art (subject category)