A couple of interesting research papers were published in the medical literature this week.
The first is from the lab of Zhigang He, of Harvard: “Sustained Axon Regeneration Induced by Co-deletion of PTEN and SOCS3.” The article was published in
Nature on-line last month but the print version came out Wednesday.
The PTEN story is one of the most interesting in the field of regeneration. Here the scientists report “robust and sustained axon regeneration” in an optic nerve model after using genetic methods to delete two factors that block regeneration. A bit of background:
In 2008 He, in Science, showed unprecedented regeneration in the optic nerve by blocking the enzyme PTEN.
In 2009, in Neuron, He showed that a protein called Suppressor of Cytokine Signaling 3 (SOCS3, “socks 3”) could also spur remarkable regeneration in the optic nerve.
In 2010, He and Oswald Steward of UC Irvine’s Reeve-Irvine Research Center, demonstrated, for the first time, that pTEN deletion allowed the corticospinal tract to regenerate. That paper was the cover story in Nature Neuroscience.
Now Dr. He and his group show, again in Nature, that a combination of PTEN deletion and SOCS3 suppression regenerates 10 times as many axons in optic nerve as PTEN or SOCS3 alone. They did the experiment in two phases, first using mutant animals that already had the inhibitors genetically blocked out before injury. The also deleted PTEN and SOCS3 after injury. Both ways boosted axon growth.
From the paper
At 2 weeks after injury, we observed a significant increase in axon regeneration in the double knockout group. The synergistic effects of the double deletion became even more dramatic at 4weeks after injury. At 2mm distal to the lesion site, deletion of both genes resulted in more than tenfold increase in the number of regenerating axons compared with deletion of either gene alone…..
Together, our experiments reveal an important strategy for achieving sustainable de novo axon regrowth in the adult CNS neurons: coactivation of specific protein translations and gene transcriptions by concomitant inactivation of PTEN and SOCS3.
This work is fascinating, and it’s tempting to draw conclusions about its clinical relevance. Much work is needed -- He and his group are far from ready to try this in people. First, they don’t know if the deletion of PTEN and SOCS3 will work as well in the spinal cord as in the eye. And then, will the regenerated axons reach appropriate targets and restore function, and will this drama include people chronic SCI?
It's fair to speculate though. Stay tuned. From the paper:
Considering the formidable long distances that regenerating axons must travel in the adult after injury, the synergistic effects of two different pathways suggest a potential solution to this challenge, making the goal of functional recovery more realistic.
The other report is from Elizabeth Bradbury and a group from King’s College in London: “Conduction Failure Following Spinal Cord Injury: Functional and Anatomical Changes from Acute to Chronic Stages,”
Journal of Neuroscience.
This experiment showed, with painstaking electrical measurement of individual nerve fibers, in a living animal, that long nerve fibers survive a spinal cord injury contusion. What’s key here is that in a chronic model (six months for rats) conduction was partly restored to by modifying the physiology of the injury area.
According to the authors, this is the first time that conduction changes in individual fibers have been assessed in vivo following spinal contusion in the adult rat.
The nerve axons were able to conduct signals after being cooled – this lowers the threshold for activating nerve potentials. But this is not an experiment about cooling or any other intervention, per se. What is shows, say the authors, is that intact surviving axons exist and are therefore targets for some type of therapy.
From the paper:
By recording antidromically activated [conduction opposite of the normal direction] single units from teased dorsal root filaments, we demonstrate complete conduction block in ascending dorsal column axons acutely (1–7 d) after injury,followed by a period of restored conduction over the subacute phase (2– 4 weeks), with no further improvements in conduction at chronic stages (3– 6 months). By cooling the lesion site, additional conducting fibers could be recruited, thus revealing a population of axons that are viable but unable to conduct under normal physiological conditions. Importantly, this phenomenon is still apparent at the most chronic (6 month) time point.
Bradbury and her team wondered whether chronic conduction block exists and, crucially, whether function can be restored to surviving axons in a chronic injury. Also, they wanted to know if demyelination played a role.
From the paper:
Importantly, by cooling the lesion site, we show enhanced conduction across the contusion injury, even in a chronic SCI. Thus, we have documented the time course over which viable but initially nonconducting axons regain a useful functionality and reveal a population of surviving axons that remain chronically unable to conduct under normal physiological conditions and that represent an important population to target therapeutically.
As for the myelin question, which is controversial in the field (some say there is no evidcence myelin is lost after SCI trauma):
In the present study, we found that despite extensive remyelination at 12 weeks after injury there remained a small but significant proportion of demyelinated axons. Importantly, we also demonstrate that, even in chronic stages of SCI, conduction can be restored to some axons upon cooling; these are most likely to be the chronically demyelinated axons observed by EM [electron microscope]. This further demonstrates the potential of viable but nonconducting axons as important therapeutic targets. Whether such therapies should involve remyelination, or other methods of reducing conduction block, remains for further study.
