Friday, 8 September 2017

Waste disposal is upregulated in MS

Autophagy - 'self-eating' - is the process by which cells degrade their own contents to prevent accumulation of intracellular waste. Waste products are enveloped by an infolding of the cell membrane, forming a contained 'vacuole'. This fuses with the lysosome - a specialised vacuole packed with digestive enzymes - which safely disposes of its cargo and releases the products for recycling. The discovery of autophagy has transformed our understanding of how cells regulate their waste. The implications of autophagy are so far-reaching that it won Yoshinori Ohsumi the Nobel prize last year. 

Neurons are particularly dependent on effective autophagy for a few reasons. They often have long projections (i.e. dendrites and axons) which are, in cellular terms, light-years away from the cell body, they are generally unable to divide, and they are metabolically active. These factors mean that neurons have a high maintenance requirement for autophagy and that this is very difficult to achieve. Unsurprisingly, dysregulation of autophagy is being recognised as a common feature of neurodegenerative diseases like Parkinson's Disease and normal ageing.That neurodegenerative disease is not universal represents a remarkable feat of waste disposal in the healthy brain.

Given that neurodegenerative is a prominent feature in MS, it is reasonable to guess that autophagy is probably going awry in this disorder as well. Is this true?

Pinton and co. tried to answer this question. They took blood and CSF samples from 40 pwRRMS, 40 people with other inflammatory CNS disease, 40 people with other non-inflammatory CNS disease, and 20 health controls. They measured levels of two markers of autophagy - ATG5 and Parkin - in these samples to see if there was an increase in the MS group.

They found that serum and CSF levels of both markers were raised in the MS group compared to the others. Both markers were correlated to levels of TNFalpha, an inflammatory cytokine, within the CSF. These findings imply that autophagy is up-regulated in MS and that this up-regulation is related in some way to CNS inflammation. However, there was no relationship between markers of autophagy and clinical disease severity.

Are these good markers? Well, ATG5 is one of many proteins involved in autophagy. Parkin - which as the name suggests is involved in Parkinson's disease - is essential for mitophagy, the sister process of autophagy in which damaged mitochondria are degraded. These markers are ok, but it would be nice to see that this effect holds true for other markers.

Nonetheless this is really interesting. It suggests that, as we'd expect, neurodegeneration in MS is accompanied by an upregulation of autophagy. They key outstanding questions for me are:
- Is this effect protective or harmful?
- Is this effect really correlated with degeneration? It'd be nice to see how autophagy markers relate to biomarkers of degeneration (neurofilament), MRI metrics (atrophy), and clinical markers (EDSS, hand function, QOL, timed walk)
- Are markers of autophagy predictive of disease progression? If so, this is another great candidate for a serum biomarker.

2 comments:

  1. It is interesting - researchers like Valter Longo suggest fasting-induced autophagy is protective somehow.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899145/

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  2. This would not be saying that constant inflammation is the major problem in MS, including in PPMS and SPMS, that MS is primarily inflammatory? And that exacerbated inflammation entails autophagy?

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