Monday, 13 November 2017

Translocator protein: useful to see, useful to target?

Translocator protein (TSPO) is found on the outer mitochondrial membrane (in other words, on the outside of the powerhouse of the cell). It is thought to be involved in regulation of several cellular processes but its actual function is still up for debate. 


TSPO became of interest because it is associated with activation of microglia (the immune cells of the brain). It was found that this activation could be visualised using positron emission tomography (PET) imaging, and so has been suggested as an indicator of neuroinflammation.


Illustrative PET and MRI images. Illustrative parametric brain PET 11C-PBR28 DVR images at baseline (A and D) from two patients with associated T2 FLAIR images at baseline (B and E) and after ∼1 year (C and F). The top panels (AC) are from a patient (EDSS 4.0) with high average NAWM DVR (1.35) (Patient A19 in Table 1). The yellow arrowhead highlights a lesion that enlarged over the observation interval. The bottom panels (DF) include images from a patient (EDSS 6.0) with low average NAWM DVR (0.88) for whom no enlarging T2 lesions were found between the baseline (E) and follow-up (F) MRI scans (Patient A5 in Table 1). The colour bar to the right of the PET images shows the dynamic range of DVR in the images (A and D). Image from: Gourab Datta et al. Brain, Volume 140, Issue 11, 1 November 2017, Pages 2927–2938,https://doi.org/10.1093/brain/awx228


In MS, these areas of neuroinflammation on PET scans correlate well with lesions found on MRI. However, pwMS also often show increased overall levels of TSPO in brain areas without lesions (see image) and the TSPO-PET can identify lesions before they appear on MRI (early stage lesions).

So, this raises the question of what exactly TSPO is showing us? TSPO has already been shown to be present on astrocytes (support cells) and may be present in other cell types too. So, what implications could this have for the PET results? This is something we are currently looking in to.

Seeing as TSPO is increased in MS lesions, could this be a therapeutic target? There are several drugs available which target TSPO, two of which I am testing as part of my project.

For now, this recent paper shows that TSPO could be very useful... 


Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis

Gourab Datta et al. Brain, Volume 140, Issue 11, 1 November 2017, Pages 2927–2938,https://doi.org/10.1093/brain/awx228
There are several different ligands (binding molecules) which can be used to visualise TSPO in PET imaging and this study uses one called PBR28. The problem with this ligand is that people commonly carry mutations which affect the binding affinity of PBR28, making them a low, moderate, or high affinity binder. This study did test for these mutations and excluded the low affinity binders, but did not then assess the data with regards to medium and high affinity binders. Could this be a problem? We're not sure yet, but again, this is something we're looking in to. 

So, TSPO is a protein which could be very useful, but there are a lot of questions still to answer...

1 comment:

  1. So what would be the effect of Benzodiazepines on MS by virtue of this increased TSPO ratio in the lesions?
    According to the TSPO is part of tryptophan-rich sensory proteins, is the relationship found in a recent study that suggested tryptophan as a possible biomarker to predict the progression of MS?

    In addition, it seems that TSPO interacts with Start (steroidogenic acute regulatory protein) to transport cholesterol in the mitochondria to stimulate the production of steroid hormones, why the oxidative stress in MS and the implication of the hormones as well?

    In some viral infections they provoke CD11b +, present in macrophages, to stimulate inflammatory infiltration. CD11b + activates immune responses and activates an increased expression of TSPO, so would that be a consequence that could become a trusted biomarker?

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