Identification of early neurodegenerative pathways in progressive multiple sclerosis

QC 20230327
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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
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

Schaupp, A. -L (author)
Sun, R. (author)
Coscia, F. (author)
Dendrou, C. A. (author)
Cortes, A. (author)
Kaur, G. (author)
Evans, H. G. (author)
Mollbrink, AnnelieKTH,Science for Life Laboratory, SciLifeLab,Genteknologi(Swepub:kth)u18ttoxc (author)
Fernandez Navarro, JoseKTH,Genteknologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u11gbovc (author)
Sonner, J. K. (author)
Mayer, C. (author)
DeLuca, G. C. (author)
Lundeberg, JoakimKTH,Science for Life Laboratory, SciLifeLab,Genteknologi(Swepub:kth)u1qkn9kw (author)
Matthews, P. M. (author)
Attfield, K. E. (author)
Friese, M. A. (author)
Mann, M. (author)
Fugger, L. (author)
KTHScience for Life Laboratory, SciLifeLab (creator_code:org_t)

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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