Biochemical and metabolic maladaption defines pathological niches in progressive multiple sclerosis

Grant-Peters, M.; Rich-Griffin, C.; Yeung, H.-Y.; Thomas, T.; Davis, S.; Azizian, M.; Fisher, J.; Fischer, R.; Cinque, G. A.; Dendrou, C. A.

doi:10.1101/2022.09.26.509462

bioRxiv · 10.1101/2022.09.26.509462

Biochemical and metabolic maladaption defines pathological niches in progressive multiple sclerosis

Grant-Peters, M.·Rich-Griffin, C.·Yeung, H.-Y.·Thomas, T.·Davis, S.·Azizian, M.·Fisher, J.·Fischer, R.·Cinque, G. A.·Dendrou, C. A.

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Abstract

Progressive multiple sclerosis (MS) is driven by demyelination, neuroaxonal loss, and mitochondrial damage occurring behind a closed blood-brain barrier (BBB).1,2 Patients with progressive MS typically fail to respond to available immunomodulatory drugs that reduce relapses in early disease.2 This indicates a dire need to identify non-canonical therapeutic avenues to limit neurodegeneration and promote protection and repair.3 Here, we have employed high-resolution multiomic profiling to characterise the biochemical and metabolic adaptations underpinning MS pathology, as these have been incompletely described but critically, may be amenable to BBB-permeable drug targeting. Using synchrotron radiation (SR)- and focal plane array (FPA)-based Fourier transform infrared microspectroscopy (FTIR), we spatially mapped the biochemical features present in human progressive MS and control post-mortem brain and rare spinal cord tissue. By employing single-nuclear RNA sequencing (snRNA-seq), 10x Genomics Visium spatial transcriptomics and spatial proteomics to resolve their cellular context, we found that these biochemical features provide a uniquely and highly disease-specific barcode for distinct pathological niches within the tissue. Characterisation of the metabolic processes underpinning these niches revealed an associated re-organisation of the astrocytic landscape in the grey and white matter, with implications for the treatment of progressive MS.

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Grant-Peters, M., Rich-Griffin, C., Yeung, H.-Y., Thomas, T., Davis, S., Azizian, M., Fisher, J., Fischer, R., Cinque, G. A., Dendrou, C. A.. 2022-09-27. Biochemical and metabolic maladaption defines pathological niches in progressive multiple sclerosis. https://doi.org/10.1101/2022.09.26.509462

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