image: Xiang-Lei Yang, professor at The Scripps Research Institute (right) and Samuel Pfaff, professor at the Salk Institute and investigator at the Howard Hughes Medical Institute, are senior authors of the new study. view more
Credit: Photo courtesy of The Scripps Research Institute.
LA JOLLA, CA - October 21, 2015 - Scientists at The Scripps Research Institute (TSRI) and the Salk Institute for Biological Studies have discovered how a mutant protein triggers nerve damage in a subtype of Charcot-Marie-Tooth (CMT) diseases, a group of currently untreatable conditions that cause loss of function in a person's hands and feet.
The new research suggests future therapies may target this haywire protein, restoring nerve function in patients with CMT.
"This is the first major advancement toward a molecular mechanistic understanding of CMT subtype CMT2D," said TSRI Professor Xiang-Lei Yang, senior author of the new study with Samuel Pfaff, a neuroscience professor at the Salk Institute and a Howard Hughes Medical Institute investigator. "These findings will help us develop future diagnostics and treatments."
The research was published online in advance of print October 21, 2015 in the journal Nature.
Solving Problems in CMT
CMT is one of the most common inherited neurological diseases, affecting about one in 2,500 people. Genetic sequencing usually turns up an array of mutations in people with CMT, making it difficult to pin down the gene responsible and develop a treatment.
In the new study, researchers focused on a protein called glycyl-tRNA synthetase (GlyRS), which is altered in people with disease subtype CMT2D.
Previous work by Yang and her colleagues showed that mutant forms of GlyRS open up their molecular structure to reveal binding components inside--a bit like opening Velcro to reveal the sticky components.
Until now, it was not clear how mutant GlyRS harmed patients.
Mutant Protein Blocks Crucial Signal
The work in Yang's lab, spearheaded by TSRI graduate student Weiwei He, revealed that mutant GlyRS can interact with the Nrp1 receptor on cells. Normally, a growth factor, called vascular endothelial growth factor (VEGF), binds to part of the receptor and relays signals to maintain nerve health.
A postdoctoral researcher in the Yang lab, Huihao Zhou, found that opened-up, mutant GlyRS can bind to the same part of the Nrp1 receptor, blocking the signals for nerve maintenance. This causes motor neurons to decline and even die, breaking the connection between the brain and muscles in the limbs. "GlyRS competes with VEGF," explained Yang.
Researchers at Salk further confirmed this finding by observing the effect of mutant GlyRS in mouse models of CMT. The team, including Salk Staff Scientist Ge Bai, used gene therapy techniques to ramp up VEGF production in mouse models. Higher levels of VEGF out-competed GlyRS, restoring function in the Nrp1 receptor. The mice with CMT regained some muscle strength and showed significant improvements in CMT symptoms.
"This solves a long-running mystery of how a gene mutation damages the neurons that carry information from the spinal cord to our muscles, resulting in a range of sensory and movement problems," said Pfaff. "It's an exciting finding, as we were able in experiments to reduce the symptoms of the disease by targeting the activity of these proteins."
Moving Toward a Treatment
The next step is to develop targeted strategies that could recognize and intercept GlyRS mutants before they block VEGF. Yang is currently working to screen possible antibodies in collaboration with Kim Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI.
The new study also has broader implications outside the subtype of CMT examined in these experiments. Yang said mutant GlyRS's abnormal interaction with Nrp1 is a crucial clue for understanding nerve damage. "This could shed light on the mechanisms behind other forms of CMT," said Yang.
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In addition to Yang, He, Bai, Zhou and Pfaff, authors of the study, "CMT2D neuropathy is linked to the neomorphic binding activity of glycl-tRNA synthetase," were Na Wei, Janelle Lauer, Yi Shi, Calin Dan Dumitru and Patrick R. Griffin of TSRI; Nicholas M. White and Karen Lettieri of Salk; Huaqing Liu and Veronica Shubayev of the University of California, San Diego; Albena Jordanova of the University of Antwerp; Velina Guergueltcheva of the Medical University of Sofia; and Robert W. Burgess of The Jackson Laboratory.
The research was supported by the National Institutes of Health, National Foundation for Cancer Research, Howard Hughes Medical Institute, Marshall Heritage Foundation, Sol Goldman Trust and aTyr Pharma.
Journal
Nature