Identification of early neurodegenerative pathways in progressive multiple sclerosis

Abstract

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 CNS disease models, supporting their causal role and value as potential therapeutic targets for 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.

Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

“…The directionality agreement of the two independent sequencing datasets validates the mechanistic concordance of our finding that IL-12 directly triggers pathways exerting pro-survival effects on the neuroectoderm. Thereby, IL-12 sensing during disease onset might counteract early neurodegenerative pathways as recently described in human MS 56 . The observation that the IL-12 receptor is expressed in both mouse and human neuroectoderm raises the possibility that IL-12 might trigger a similar reparative mechanism also in the human CNS.…”

Exosomes as CNS Drug Delivery Tools and Their Applications

“…One study [ 75 ] reported that intravenous administration of microglia exosomes harboring miR-124-3p could target neurons and alleviate neurodegeneration. Multiple sclerosis (MS) is a classic neuroinflammatory disorder mainly characterized by inflammatory demyelinating lesions in the white matter of the CNS [ 174 ]. The LJM-3064 aptamer, which was chemically covalently bound to the surface of MSCs exosomes, significantly ameliorated neuroinflammation by reducing areas of demyelinating lesions in the spinal cord and brain [ 84 ].…”

Spatiotemporal orchestration of multicellular transcriptional programs and communications in the early stage of spinal cord injury

“…( n ) GO term analysis of the unique and shared DEGs (left) and the heatmap showing the average normalized expression levels of the DEGs (right) associated with the three spatiotemporally-defined groups of astrocytes-WM,-GM and -GMii. The DEGs that are cross-referenced as pro-inflammatory (red), trophic (red) or protective (in bold) genes (Kaufmann et al, 2022) are highlighted. ( o ) The UMAP re-projection of the astrocytes- Gfap in the scRNA-seq dataset (Milich et al, 2021) reveals 5 casual sub-clusters.…”