Saturday, 2 July 2016

Cholesterol Gene pathway is altered in progressive disease in Mice

Sevastou I, Pryce G, Baker D, Selwood DL. Characterisation of Transcriptional Changes in the Spinal Cord of the Progressive Experimental Autoimmune Encephalomyelitis Biozzi ABH Mouse Model by RNA Sequencing. PLoS One. 2016 Jun 29;11(6):e0157754. doi: 10.1371/journal.pone.0157754. eCollection 2016.

Multiple sclerosis (MS) is a debilitating immune-mediated neurological disorder affecting young adults. MS is primarily relapsing-remitting, but neurodegeneration and disability accumulate from disease onset. The most commonly used mouse MS models exhibit a monophasic immune response with fast accumulation of neurological damage that does not allow the study of progressive neurodegeneration. The chronic relapsing and secondary progressive EAE (pEAE) Biozzi ABH mouse model of MS exhibits a reproducible relapsing-remitting disease course that slowly accumulates permanent neurological deficit and develops a post-relapsing progressive disease that permits the study of demyelination and neurodegeneration. RNA sequencing (RNAseq) was used to explore global gene expression in the pEAE Biozzi ABH mouse. Spinal cord tissue RNA from pEAE Biozzi ABH mice and healthy age-matched controls was sequenced. 2,072 genes were differentially expressed (q<0.05) from which 1,397 were significantly upregulated and 675 were significantly downregulated. This hypothesis-free investigation characterised the genomic changes that describe the pEAE mouse model. The differentially expressed genes revealed a persistent immunoreactant phenotype, combined with downregulation of the cholesterol biosynthesis superpathway and the LXR/RXR activation pathway. Genes differentially expressed include the myelination genes Slc17a7, Ugt8A and Opalin, the neuroprotective genes Sprr1A, Osm and Wisp2, as well as genes identified as MS risk factors, including RGs14 and Scap2. Novel genes with unestablished roles in EAE or MS were also identified. The identification of differentially expressed novel genes and genes involved in MS pathology, opens the door to their functional study in the pEAE mouse model which recapitulates some of the important clinical features of progressive MS.

There are some of you out there that think that animal models are useless and a waste of time. Others think that they are vital for the development of treatments.  

EAE has taken a bashing because it has turned up so few treatments. I will argue that it takes time for these treatments to filter through. Also the issue is the way we use the data from the animal work and how it is then translated by humans, whether the researchers or the clinicians, pharmaceutical, conspires to lead to failure. This maybe because the idea was hopelessly wrong in the first place.

I have had recent dealing with some animal modellers doing testing in non-MS areas ,where their positive control in the experiment only worked at 70 times the human dose and no other drug currently used in the human disease could work in the test system. I would say in dutch:-) "Schtop". The testing isn't fit for purpose. 

So we can improve in how we use animals...however as the UK get more isolated, our passion for 3Rs and ethical use of animals in experiments and care of farm animals gets diluted by the people who don't care and these people exist in many countries

There are people out there that believe there are no models of progressive MS. They are simply wrong. We have one and following a period of relapses progressive disease ensues that no longer responds to drugs that block relapsing disease.

In this study we can simply ask what is the difference of the genes being activated to make proteins in progressive disease compared to health. There are many thousands of genes that are different and this will be in part due to the presence of immune cells in the CNS.

RNAseq (R, N, A, seek) detects the sequences of the RNA that has been made from DNA and tests every gene in the body and it is perhaps amazing that only about 2000 genes were deferentially expressed and interestingly the pathway that popped out of this "fishing trip" look-see was the cholesterol pathway. Maybe this starts to underpin why statins may have use in progressive MS.  If we look in Alzheimers disease where nerves are lost, the cholesterol pathway also features heavily. This contains loads of data and it will be hard to fathom what is occurring until be do more such as see what happens when we add immune cells into the mix. Maybe this is telling use something.

However the real reason why we did the experiment was to see what was the difference between the animals with progressive disease and what happens when we give a drug of interest to animals with progressive disease. What changes? 

The answer was only seven genes and some of then were in the same pathway, what was this and what were they and what is this secret until we do more work.

CoI: This is our work


  1. Excellent post MD! How do you hypothesize cholesterol causes neuron death or worsens neurodegeneration?

    1. I don't know maybe lipid/fatty acid metabolism

  2. I liked that MD. o//
    I know it's top secret, but then there would be such an implication also the environment in MS genetics, especially n-progressive?

    Vitamin D appears to help regulate cholesterol, healthy intestinal microbiome appears to help regulate cholesterol, infection with Epstein Barr virus appears to alter the levels of cholesterol mainly in the acute phase of infection, and sex hormones interfere with the pathway of cholesterol...
    Then the MS could be a disease of multifactorial spectrum converging to the same pathway, the genes that regulate cholesterol...

  3. I used to see cholesterol and fat metabolism in a expression from cell autonomous (i.e. primary, not infiltrating) immune response in the model i worked on in grad school. I'm convinced that there's more to tissue stress and distress and defence than the canonical stat + nfkb stuff, and that this was part of it.

    10 bucks says that's what you're seeing too.

  4. That's quite interesting since cholesterol has been implicated in other neurodegenerative disorders. And if I recall correctly, cholesterol and oxidised forms of cholesterol can have an impact on the mitochondria, which could also contribute to neuronal cell death


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