New Insights into Nerve Regeneration
Nerve regeneration is the Holy Grail of medical neuroscience. The traditional dogma is that in humans — unlike other animals — nerve regeneration simply does not occur. We start life with those 80+ billion neurons in the brain, and after that all we see is neuron death, not regeneration.
This traditional dogma has now been shown to be wrong. New neurological procedures are designed to reconnect large fiber bundles in the spinal cord. One discovery is that broken neurons may not regenerate, unlike other body tissues, because the very process of wound inflammation and scar formation inhibits regeneration. If a molecule can be found to “inhibit the growth inhibitor” neurons might regrow. This approach appears to work in many cases, giving real hope for the future. Neuron loss is a major feature of Alzheimer’s Disease, Parkinson’s, and other degenerative brain conditions. Stroke and head injury also show large neuron losses, and even the subtle longterm brain damage that boxers and football players risk involves widespread (but microscopic) breakage of neurons. (Called Minimal Brain Damage).
A PLOS BIOLOGY article by Vilar et al (2014) now pinpoints a new molecular mechanism of growth inhibition, and a treatment that involves inhibition of inhibition.
An editorial in PLOS Biology writes that,
“Axons rarely regrow after a severe spinal cord injury, in part because of inhibitory signals associated with myelin, which surrounds and insulates the axon. These signals bind to the Nogo receptor, which can then bind to a variety of co-receptors, including a protein called p75. Together, this complex triggers a cascade of intracellular signals that ultimately inhibits axonal sprouting and prevents regeneration. Understanding how p75 is regulated, therefore, may shed light on new strategies for promoting recovery from nerve damage. In this issue of PLOS Biology, Marçal Vilar, Tsung-Chang Sung, and Kuo-Fen Lee show that p75 may lose its affinity for the Nogo receptor through interaction with a second protein, whose structure is closely related to p75 itself.”
Figure 1 shows the dance of molecules in a simplified cartoon. On top is a broken axon (the horizontal beads are myeline cells). On the left is the natural process, in which myelin inhibits regeneration of the axon, using a molecule and receptor called “myelin associated inhibitor” called Nogo, which fits into a receptor called Nogo Receptor, or Ng#R. When the protein P45 is added to the neuron culture, it inhibits Nogo/NgR, and allows the axon to regrow.
For a century neuroscientists have believed this is impossible in humans. A very deep understanding of the molecular dance of cell breakdown and recycling is now bringing hope for unprecedented medical advances.