Saturday, 23 November 2013

Sometimes being thick helps

Fyffe-Maricich SL, Schott A, Karl M, Krasno J, Miller RH. Signaling through ERK1/2 Controls Myelin Thickness during Myelin Repair in the Adult Central Nervous System. J Neurosci. 2013 Nov;33(47):18402-18408.

Oligodendrocytes, the myelin-forming cells of the CNS, exquisitely tailor the thickness of individual myelin sheaths to the diameter of their target axons to maximize the speed of action potential propagation, thus ensuring proper neuronal connectivity and function. Following demyelinating injuries to the adult CNS, newly formed oligodendrocytes frequently generate new myelin sheaths. Following episodes of demyelination such as those that occur in patients with multiple sclerosis, however, the matching of myelin thickness to axon diameter fails leaving remyelinated axons with thin myelin sheaths potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes determine the appropriate thickness of myelin for an axon of defined size during repair is unknown and identifying the signals that regulate myelin thickness has obvious therapeutic implications. Here, we show that sustained activation of extracellular-regulated kinases 1 and 2 (ERK1/2) in oligodendrocyte lineage cells results in accelerated myelin repair after injury, and is sufficient for the generation of thick myelin sheaths around remyelinated axons in the adult mouse spinal cord. Our findings suggest a model where ERK1/2 MAP kinase signaling acts as a myelin thickness rheostat that instructs oligodendrocytes to generate axon-appropriate quantities of myelin.

This is is interesting as it shows you a mechanism to repair myelin with similar thickness to normal myelin.
Extracellular-signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of cell division and  cell functions.. Many different stimuli, including growth factors, cytokines, virus infection, activate the ERK pathway.

The term, "extracellular-signal-regulated kinases", is sometimes used as a synonym for mitogen-activated protein kinase (MAPK), but has more recently been adopted for a specific subset of the mammalian MAPK family. In the MAPK/ERK pathway, Ras activates c-Raf, followed by mitogen-activated protein kinase kinase. ERKs are known to activate many transcription factors.

Whilst this is really interesting the question is howto exploit this knowledge. These signalling molecules are used by loads of different cell types to do lots o things. This is a common problem for a lot of the remyelination factors in oligodendrocytes. They are common in alot of other cell types so the change of side effects is high. However, as we know that in MS and EAE the lesions have plenty of immature oligodendrocyte cells near them but they are not differentiating, maybe we only need a short treatment pulse to push the cells to remyelinate rather than years of treatment. With a short pulse of treatment side effects may be more acceptable if the ends justify the means.

1 comment:

  1. Yes this is very interesting but as you mentioned these kinase signaling pathways are ubiquitous and the fear of side effects such as uncontrollable cell growth is real. How to target these pathway "switches" for a particular cell type such as OPCs....maybe stimulate them in a dish and transplant?


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