Neuronal vulnerability and multilineage diversity in multiple sclerosis. Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, Rowitch DH. Nature. 2019 Jul 17. doi: 10.1038/s41586-019-1404-z. [Epub ahead of print]
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing–remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
Broadly defined, projection neurons are neurons whose axons extend from the neuronal cell body within the central nervous system (CNS) to one or more distant regions of the CNS.
The new powerfull techique is single nucleus sequencing so you get a genome profile of every individual cell. This is great but the problem is you have to do thousands and thousands of cells to get an idea of what is going on, as your selection of cells will determine what you find.
There was loss of excitatory nerves under areas of meningeal infiltration suggesting that the inflammation can be important. However as these are projection neurons remember the damaging event may be very far away perhaps leading to the idea of the degenerating cortical lessions on the outside of the brain that are not demyelinating.
The T cell immunologists will be one the case and they will be sequencing thousands of cells to get their T cell receptors in the hold that they can find the specific antigen. Will they rememebr that is likely that most T cells will be just bystander cells, called into the inflammatory lesion due to their expression of adhesion molecules and chemokine receptors. Will they find MBP (myelin basic protein) reactive T cells. I bet they will because they will be looking for them. But is that the major problem or a secondary epiphenomenon due to previous damage liberating MBP.
Then there is the hoover microglia who clean the debris to allow repair to occur
They say they find transcriptional profiles of the cells that relate to the progression of the lesion, however you have toalso remember that the genes they can find is secondary to the cells they find so if there are macrophages there, then there are macrophage genes there. It doesn’t prove cause and effect.