For SMA, growth factor NRG1-III improved nerve fibers in mice
Study shows nerve impairment can be treated other than by increasing SMN protein
Boosting the production of the growth factor protein NRG1-III improved motor nerve fiber development in the early stages in a mouse model of spinal muscular atrophy (SMA), a study showed.
NRG1-III was unable to prevent nerve fibers from degenerating or improve motor function or survival in older mice, however.
The work provides a proof-of-principle that nerve impairment in SMA can be mitigated by treatment approaches independent of increasing the levels of survival motor neuron (SMN) protein, the researchers wrote in “Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation,” which was published in Acta Neuropathologica Communications.
People with SMA are deficient in SMN, a protein needed for the function of motor neurons, the nerve cells that control voluntary muscle movement. Many SMA treatment strategies seek to increase SMN levels to improve motor neuron health and ease symptoms.
Researchers at the Johns Hopkins University School of Medicine, Maryland demonstrated that motor axons, the nerve fibers of motor neurons, developed more slowly in severe SMA patients and SMA mice. Their growth was often stalled, with smaller diameter and slower electrical transmission speeds. There were also fewer Schwann cells that produced myelin, a fatty, protective coating surrounding motor axons required for a rapid signal transmission.
However, “the molecular mechanisms underlying impaired motor axon maturation in SMA are unknown,” the researchers wrote.
Neuregulin 1 (NRG1) is a growth factor protein that’s essential in nervous system development and nerve repair. NRG1-III is the major form of the NRG1 family in motor neurons and is necessary for Schwann cell growth and survival, as well as the myelination of axons.
Role of NRG1-III in motor axon development
The researchers investigated the role of NRG1-III in the development of motor axons in tissue from SMA patients and in an SMA mouse model.
Tissue samples collected from SMA type 1 patients and 1-day-old mice showed a significant reduction in the activity of the gene that encodes NRG1-III compared with control samples. By contrast, NRG1-I, another form of NRG1 produced in Schwann cells during the myelination of nerves, was unchanged.
These findings prompted researchers to engineer an SMA mouse to overproduce the protein. Boosting NRG1-III made motor axons 177% thicker in early developing SMA mice and increased the number of myelinated axons by 272% and the number of Schwann cells by 89%, similar to levels in healthy mice.
The high activity of NRG1-III didn’t change the total number of axons in SMA or control mice, an electron microscopy analysis showed.
Still, in SMA mice, there was a 437% increase in the number of myelinated axons and a 98% increase in the number of segregated axons, indicating “that NRG1-III not only reinstated myelination of axons, but also partially restored the sorting/segregation of axons by Schwann cells into the one-to-one relationships required for myelination,” the researchers wrote.
Boosting NRG1-III in SMA mice also restored the thickness of axons and the percentage of myelinated axons to a normal range diameter.
While excess NRG1-III improved signal speed across motor axons in SMA mice, it couldn’t boost responses to those signals in muscles.
There were also no improvements in the number of nerves that supply the neuromuscular junction, the place where axons connect with muscles, indicating “NRG1-III overexpression does not suppress degeneration of the distal [farthest] motor axon in SMA mice,” the researchers wrote.
Boosting NRG1-III also didn’t provide sustained benefits in SMA mice. In fact, mouse survival was shortened with excess NRG1-III. Also, no improvements were seen in nerve signals and axon thickness between two and 14 days of age, “likely due to ongoing axon degeneration mitigating any developmental gains,” researchers said.
“Here we identify NRG1-III as a key molecular determinant of impaired motor axon segregation and myelination in SMA,” they said. “We demonstrate that boosting NRG1-III expression accelerates several steps of SMA neonatal motor axon maturation.”
The study shows the “potential of targeting developmental pathways downstream of SMN protein deficiency as a means to ameliorate aspects of disease pathology that cannot be reversed by postnatal SMN protein induction alone,” they said.