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This study (Anderson et al. 2020) tested a FOXP1 knockout model in mice. FOXP1 is a gene that is important in the development of the striatum and has been linked to autism and intellectual disability. The study found that deleting FOXP1 led to more 2-4 fold increases in eMSN. So the idea is...

Some useful links for the Belgian context of ME/CFS: https://www.me-gids.net/ https://12me.be/ https://www.millionsmissingbelgique.com/ https://www.wucb.be/

One caveat is that the eMSN data is relatively new, discovered in 2018 and included in the human brain atlas in 2023. So a lot of GWAS from other diseases might not have tested for this cell type yet. Perhaps if they did, it would be connected to a lot of brain diseases and behavioral traits...

Think it's worth looking into these other cell types as well. Seems like there's a link to splatter cells as well which are also poorly understood. I also have a question @tralfamadorian97: does the signal for Amygdala excitatory (Cluster419) point to the amygdala's intercalated cells. Cause...

Possibly, but their paper mapped out the entire brain, and their data is relevant for 100s of medical conditions. It wasn't focused on eMSN in particular; they just happened to find it when mapping the entire brain. But with eMSN being largely unknown and there being a connection to ME/CFS, I...

A clarification that I didn't notice before: the human atlas mentions that most eMSN only have DRD1. Those with both DRD1 and DRD2 were a regional specialization in the basal ganglia. EDIT: here's figure 2 form the supplementary material:

The next major data source is the brain atlas by Siletti et al. 2023. Transcriptomic diversity of cell types across the adult human brain - PubMed They did the same single-cell RNA sequencing of the brain but in 3 human donors. They found 461 clusters for cell types, but there were also 31...

On the topic of links to the striatum, next to eMSN, HTT, and GPR52, there's also TSHZ3, which was a significant hit in Paolo's meta-analysis (not DecodeME alone). A bit more speculative perhaps, but knockout experiments of these genes in mice found changes in corticostriatal glutamatergic...

Yes, but it also came up in DecodeME itself https://www.s4me.info/threads/genetics-chromosome-1-rabgap1l.45502/post-693850 It's in the RABGAP1L region, but given what we know now about eMSN , GPR52 might be a more likely candidate. From what I understand, it's a receptor that modulates...

PCDH8, which plays a role in synaptic reorganization and down-regulation of dendritic spines. PCDH8 Gene - GeneCards | PCDH8 Protein | PCDH8 Antibody It's on chromosome 13. We thought that the DecodeME signal there pointed to OLFM4, as it is closer, but the fibromyalgia GWAS also found a signal...

Zooming in on the Saunders et al. 2018 paper that discovered eMSN. Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain - PubMed This was a major study where they built a brain-wide cell atlas of mice by extracting tissue and profiling individual cells' RNA using...

Agree, although I think the evidence suggests these cells are likely to play a key role in ME/CFS pathology.

Some speculation about this: - Perhaps some eMSN are in close enough proximity and well enough connected (e.g. those in the nucleus accumbens) to influence the hypothalamus - Perhaps eMSN CRH has influences through the ventricles - Perhaps there is a middle-man that interprets the excess of CRH...

My guess is that a little bit of CRH stimulates production, a bit like seeing other footballers on the pitch as a sign that the game has started. But that too much CRH gives negative feedback as so often happens in biology, a bit like seeing too many football players on the pitch already, so you...

Thanks! Perhaps this thread would be more suitable for discussing the CRH connection, because it's more of a side issue in the eMSN finding. I was thinking about a hypothesis taking the following steps: - Genetic data suggests that eMSN are the main cell type in ME/CFS pathology - The current...

@tralfamadorian97 is also doing interesting analyses using the DecodeME data, including the MAGMA analysis that links DNA results of ME/CFS patients to gene expression (scRNAseq) data from the Human Brain Atlas. So this is similar to what Paolo did, but with only the DecodeME data (not those...

Thanks, I see this as confirmation that the data really points to eMSN and that it wasn't a fluke or error from the meta-analysis Paolo did.

@jnmaciuch When you have time/energy, would also be interested in your opinion on the brain imaging studies on fatigue during sickness behavior pointing to the left nucleus accumbens and putamen. The ME/CFS genetic data seems to highlight the striatal region with genes such as TSHZ3, GPR52, HTT...

Hmm, think this overstates it a little because there are likely tons of cell types that do not produce CRH as prominently as eMSN. Genetic data suggests that eMSN are the main cell type that is overfiring and they probably have CRH as co-factor. So if this theory is true, there would be too...

Thanks for sharing this. My counterpoint would be that the genetic data is pointing to eMSN cells (all over the body) as key to ME/CFS pathology. The CRH is just an extra bonus that could make the autopsy findings fit. So it doesn't matter that match if other cells can make CRH as well, because...