Glaucoma. Optic neuritis. Trauma of the optic nerve. All of these conditions may irreversibly damage the optic nerve, leading to blindness. Glaucoma alone affects more that 3 million people in the US. Nerve damage (es. due to spinal cord injury) leading to paralysis is similarly common, with around 5 million people in the US living with several forms, according to the Christopher Reeve Foundation. Although blindness and paralysis may seem very different, many types of these two conditions share the same underlying cause: nerves whose axons (the fibers that connect the nerve to the brain or spinal cord) are severed and are hindered for growing back. Axons act like wires, transmit electrical impulses from neurons to various parts of the body. If a wire is cut, it cannot transmit signals and the connection goes dead. This situation happens also in multiple sclerosis, which affect nearly 1 million americans.
Injuries to the nerves can blind or paralyze because adult nerve cells don’t regenerate their connections. Some animals can regrow axons, but mammals such as mice and humans cannot. It was assumed that mammals lack the immature nerve cells that would be needed. Now, a team of UConn School of Medicine researchers report in Development that at least a small population of nerve cells exist in everyone that could be committed to regrow and restore sight and movement. They express a similar subset of genes, and can be experimentally stimulated to regrow long-distance axons. Moreover, the researchers found that mitochondria-associated DynLT1A and LARS2 proteins were upregulated in injured neurons during experimental axon regeneration, and that activating them through gene therapy in these neurons promoted axon regeneration.
Researchers believe that similar immature nerve cells exist in regions of the brain outside the visual system too, and might also heal some features of paralysis under the right circumstances. The right circumstances are difficult to provide, though. Once stimulated by a treatment, these embryonic-like nerve cells’ axons start to regrow in injured areas, but tend to stall before they reach their original targets. Previous research has shown a combination of cell maturity, gene activity, signaling molecules within the axons, as well as scarring and inflammation in the injury site, all seem to inhibit axons from regrowing. Some therapies that target genes, signaling molecules, and injury site environment can encourage the axons to grow somewhat, but they rarely grow long enough. This is why researchers began looking at how oligodendrocytes were behaving.
If axons are the wires of the nervous system, oligodendrocytes make the insulation called myelin. It insulates the axons, improves conductivity and also prevents the axons from growing extra, extraneous connections. Typically axons in embryos grow to their full length before they are coated with myelin. But scientists found that in these injury sites, the cells that apply myelin start interacting with the regenerating axons shortly after they begin growing. That interaction, which precedes the insulation process, contributes to the axons stalling out, so that they never reach their targets. The researchers suggest that a multi-pronged approach would be needed to fully regenerate injured axons. Therapies that target both the gene and signaling activity within the nerve cells would be necessary to encourage them to grow as an embryonic nerve cell would.
And clearing the environment of inhibitory molecules and pausing oligodendrocytes from insulating, would give the axons time to reconnect with their targets in the brain before becoming myelinated. Then, drugs or other treatments that encourage oligodendrocytes to myelinate the axons would complete the healing process. The tumor suppressor gene Pten is one of the most potent gene regulators of axon regeneration discovered to date. PTEN suppresses axon regeneration through inhibition of the mTOR pathway, and Pten knockout was shown to promote various extents of axon regeneration from neurons in the retina. In this investigation scientists found that by pharmacological and genetic inhibition of phosphatase PTEN upregulated mitochondria-associated genes DynLT1a and Lars2, which promote axon regeneration on their own.
In previous researches, the swedish team found that expression of the axon regeneration-facilitating TET1 demethylase (which is controlled by embrional factors like Sox2 and KLF4) is substantially downregulated in the injured retinal neurons, but its expression is preserved (and even modestly upregulated) in those that responded to Pten KD. Moreover, the Sox2 component of that treatment, is upregulated in the long-distance axon-regenerating retinal neurons that responded to Pten KD. Finally, other science teams found that several other known axon regeneration-promoting genes were also upregulated in the long-distance axon-regenerating retinal neurons by Pten KD, including singaling proteins IGF-1R, B-Raf and c-Akt3. The new insights into how axons grow could someday create a path for truly effective therapies for blindness, paralysis and other disorders caused by nerve damage.
But for the research team, in addition, these informations answer some of the big questions of how our nervous systems develop, by understanding the molecular mechanisms behind both axon growth and interaction with oligodendrocytes.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Clinical Biochemistry.
Scientific references
Rheaume BA et al. Development. 2023; 150(8):201644.
Campion TJ, Sheikh IS et al. Exp Neurol. 2022; 349:113961.
Jacobi A, Tran NM, Yan W et al. Neuron 2022; 110:2625-45.
Lu Y, Brommer B, Tian X et al. Nature 2020; 588:124-29.
Restor Neurol Neurosci. 2019; 37(6):545-52.