Proteins Involved in Nervous System Development May Guide Understanding of CMT2D Motor Impairment

Proteins Involved in Nervous System Development May Guide Understanding of CMT2D Motor Impairment

Researchers have discovered that a molecular mechanism involving critical proteins for nervous system development may help explain targeted neuromuscular defects in Charcot-Marie-Tooth disease type 2D (CMT2D).

The study titled, “Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy,” appeared in the journal Frontiers in Molecular Neuroscience.

CMT2D is caused by mutations in the GARS gene, which codes for the protein GlyRS. GlyRS belongs to a group of enzymes that mediate the binding of amino acids — the building blocks of proteins — to RNA in gene expression.

Although research has shown that GlyRS is essential in almost all cell types, CMT2D is characterized by damage to nerve fibers, leading to progressive muscle weakness. The exact mechanisms explaining this specificity remain unknown.

Mutations in GARS lead to structural changes in the GlyRS protein, which can make it bind to new targets both within and outside cells. One of these unusual targets is a protein called neuropilin 1 (Nrp1). Nrp1 binds to other extracellular proteins, such as semaphorins and plexins, to guide the development of both cardiovascular and nervous systems.

The interaction of mutant GlyRS with Nrp1 blocks the cellular effects of vascular endothelial growth factor (VEGF), a protein that stimulates the formation of new blood vessels. This impact on VEGF is mostly observed in the nervous system and may contribute to CMT2D.

In addition to a loss of nerve fibers, mouse models of CMT2D also exhibited impaired neuronal communication at the neuromuscular junction (NMJ), the site where motor neurons and muscles connect. The plexin-semaphorin interaction regulates this communication, as well as maturation of synapses, which are also damaged in mice with CMT2D.

Studies in flies showed that mutant GlyRS acts on the NMJ, leading to degeneration and abnormal development of the flies’ nervous system. Although the exact pathway driving this effect is unknown, the research team hypothesized that the neuropilin-plexin-semaphorin interaction could be involved.

Results showed that production of mutant GlyRS led to similar alterations in nerve fibers as mutations in the fly variants of the plexin genes – plexA and plexB.

The data also show that reducing the expression of plexA and plexB increased and decreased the viability and motor deficits caused by mutant GlyRs, respectively. This approach also altered the localization of proteins in nerve fibers.

Specific reduction of plexB reduced the accumulation of GlyRS in the synapse. In turn, augmented production of the protein that binds to PlexB, called semaphorin-2a (Sema2a), minimizes the interaction of mutant GlyRS with the synapse and the associated motor defects. No changes were observed after increasing the production of the plexA binding protein Sema1a.

“Taken together, these data highlight the importance of plexin-semaphorin signaling in the regulation of mutant GlyRS toxicity and accumulation, and the role of the PlexB-Sema2a on mutant GlyRS synaptic build-up,” the researchers wrote.

“Our findings provide additional evidence of a new disease paradigm in CMT2D, which provides further explanation for the selective effect on the nervous system of mutations in a widely expressed protein,” they added.

One comment

  1. Albert Algar says:

    will taking over the counter protein (like whey protein)help if you have CMT-1A?

    is there a way to control the tremors in hands and body?

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