Nerves of the central nervous system may begin flexing regenerative powers if they can be induced to express a protein normally found in muscle cells. These nerves won’t even have to submit to any grueling exercise routines. Instead, they may benefit from gene therapy, a new study suggests.
According to a team of scientists based at Ruhr University of Bochum, overexpression of muscle LIM protein (MLP) could become a therapeutic strategy for promoting the repair of nerves in the brain, the optic nerve, and the spinal cord. To demonstrate this possibility, the scientists, led by Dietmar Fischer, PhD, tried retarding and boosting the expression of MLP in a rat model of nerve injury, a model in which the optic nerve had been crushed.
The results of the scientists’ work appeared January 22 in the journal Cell Reports, in an article titled, “Muscle LIM Protein Is Expressed in the Injured Adult CNS and Promotes Axon Regeneration.” The article reported that MLP expression is induced in adult rat retinal ganglion cells (RGCs) upon axotomy, and that the expression of MLP is correlated with the ability of RGCs to regenerate injured axons.
“Specific knockdown of MLP in RGCs compromises axon regeneration, while overexpression in vivo facilitates optic nerve regeneration and regrowth of sensory neurons without affecting neuronal survival,” the article’s authors wrote. “MLP accumulates in the cell body, the nucleus, and in axonal growth cones, which are significantly enlarged by its overexpression.”
Extra MLP, the scientists emphasized, helped the RGCs do some of the heavy lifting needed for nerve regeneration. Essentially, the MLP gathered in the tips of nerve fibers, where it stabilized the structures in so-called growth cones.
“Only the MLP fraction in growth cones is relevant for promoting axon extension,” the article continued. “Additional data suggest that MLP acts as an actin cross-linker, thereby facilitating filopodia formation and increasing growth cone motility.”
MLP, which in the current study emerges as a kind of molecular Atlas, was identified as a potential target in therapeutic development in earlier studies by the Ruhr University team. Specifically, in studies of the relationships between inflammatory stimulation, gene expression, and regenerative capacity, the team screened microarrays for genes that are expressed differently in injured and uninjured nerves.
MLP plays a crucial role in the cells of cardiac and skeletal muscle tissue, but it is also produced in the nerve cells of the central nervous system under certain conditions. In the current study, the scientists demonstrated that the production of MLP in neurons is induced if they had been artificially stimulated to grow nerve fibers.
If the researchers blocked the protein’s function or suppressed its production, the nerve cells’ ability to grow axons was significantly reduced. If, conversely, the researchers deployed gene therapy to cause damaged nerve cells to produce MLP, the respective axons showed a significant increase of their regenerative ability. In animals, axon growth in the injured optic nerve was thus considerably boosted when compared to animals that didn’t undergo the therapy.
Injuries or diseases of nerves in the central nervous system result in lifelong disabilities, such as paraplegia caused by damage to the spinal cord or blindness following the injury of the optic nerve. “Nerve regeneration therapies for clinical applications are not available yet,” pointed out Fischer. This is because nerve fiber—so-called axons—either don’t produce any proteins that are essential for their regeneration at all, or they don’t produce enough of them.
“If we identify such proteins and trigger their production using gene therapy, we’d have novel, applicable methods for nerve regeneration at our disposal,” Fischer declared. Mechanisms similar to the one explored in the current study may promote the regeneration in other regions of an injured brain or spinal cord, he noted.
