More on manipulating olligos to save nerves
Schirmer L,
Möbius W, Zhao C, Cruz-Herranz A, Ben Haim L, Cordano C, Shiow LR, Kelley KW,
Sadowski B, Timmons G, Pröbstel AK, Wright JN, Sin JH, Devereux M, Morrison DE,
Chang SM, Sabeur K, Green AJ, Nave KA, Franklin RJ, Rowitch DH.Elife. 2018 Sep 11;7. pii: e36428. doi: 10.7554/eLife.36428.
Glial support is critical for
normal axon function and can become dysregulated in white matter (WM) disease.
In humans, loss-of-function mutations of KCNJ10, which encodes
the inward-rectifying potassium channel KIR4.1, causes seizures and progressive
neurological decline. We investigated Kir4.1 functions in oligodendrocytes
(OLs) during development, adulthood and after WM injury. We observed that
Kir4.1 channels localized to perinodal areas and the inner myelin tongue,
suggesting roles in juxta-axonal K+ removal. Conditional
knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial
damage and axonal degeneration. This was accompanied by neuronal loss and
neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by
delayed visual evoked potentials, inner retinal thinning and progressive motor
deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after
WM injury in the spinal cord. Our findings point towards a critical role of
OL-Kir4.1 for long-term maintenance of axonal function and integrity during
adulthood and after WM injury.
Kir
4.1 channels are interweaved with MS research. Many years ago it was suggested
that about half of the people with MS had antibodies reactive with this
potassium channel. Roll forward and many papers later that cannot replicate the
finding and we have the very same channel being reported to be critical in
oligodendrocyte function. Loose the channel and you get seizures, probably
because nerve excitability is not controlled. They knocked it out in
oligodendrocytes and it resulted in nerve loss and if there was nerve damage
this was made worse. So maybe we have a treatment avenue.
I suspect there are lots of treatment avenues with regard potassium
channels, indeed we showed that a big conductance potassium channel opener has
the potential to be neuroprotective. This moves
potassium in a similar way to the inwardly rectifying potassium channels. It
has been shown that oligodendrocyte precursors form a synapse with
non-myelinated nerves in a process involving
glutamate receptors, who functions via calcium ion movement to stimulate
myelination. Potassium channels will regulate this ionic function and so loss
of potassium channels could be bad news as suggested here. However this may not
be the only channel (nerve transmitter). Immature oligodendrocytes express
looks and lots of ions channels including calcium and sodium channels. They
also express loads and loads of potassium channels. As they differentiate into
oligodendrocytes they down regulate most of them, but kcnj10 is still there maybe it can be manipulated to save nerves