The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons.
To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes.
Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials.
In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted.
We have reported on this very experiment before but, rather than making a splash in the media, this new report does not make much of a trickle.
The authors will be rather sad that they were pipped-at-the- post by the Swiss group reporting on this a few months ago. This shows that you do not have ideas in isolation and other people will do the same thing once you have a tool to address the question.
I thought about this experiment years ago and wondered what would happen if you could devise a way to kill oligodendrocytes. I thought it would cause unacceptable severity of neurological symptoms leading to rapid death and so it has been proved a reality in this current and past study.
This study uses a gentically engineered mouse where they can kill the myelin-forming cells and looks to see what happens. The mice get a neurological disease and die. This is too quick for it to be of much real use to inform about MS. But they report on nerve dysfunction in the absense of myelin loss.
This is not surprising as we knew this already that:
- If you get oligodendrocyte death such as occurs in stroke in humans, you do not get MS!
- Therefore, you would not expect this to occur in the models
So whilsts the authors of the past study seek new jobs, because they do not think their studies are worthwhile………so it would be hypocritical to keep working on this subject, if you do not believe in the work you are doing 🙂 we will look at this new study
In the past study they infered that demeylination can cause new loss, but we suggested that they (the original study) did not show any demyelination, despite the inferences of the author and it is therefore of interest that this current study shows that neurological problems and nerve loss occurs in the absence of being able to detect overt demyelination (stripping of the myelin sheath off the axon). Therefore the referees of the first study were sort of hood-winked.
The new study reports that if you kill oligodendrocytes, neurological problems occur and this is associated with nerve damage, but this does not need overt demyelination. They suggest this is an additional damaging mechanism that is important for MS.
This may be the case, however, this could also be something that is abit of a mouse thing!, Mice do not show very good demyelination, in comparison to other species…..once the myelin goes the nerve goes very quickly…This has been noted in mice (notably C57BL/6 strain which has a propencity to show nerve loss) in alot of other studies.
It shows us that myelin loss is not everything in terms of problems in MS