Summary: New research from Scripps Research links the severity of Charcot–Marie–Tooth (CMT) disease to how much certain aminoacyl-tRNA synthetase enzymes adopt an open, extended conformation rather than to loss of their core aminoacylation activity.
Source: Scripps Research Institute
Overview
Charcot–Marie–Tooth (CMT) disease is a genetically diverse peripheral neuropathy that damages nerves reaching into the hands and feet, producing symptoms such as balance problems, difficulty walking, and impaired fine motor skills like buttoning a shirt. More than 90 different genes have been linked to CMT; a single pathogenic mutation in any one of these genes can cause disease. Because of this genetic complexity, developing broadly effective treatments has been challenging.
Study focus and approach
Researchers at Scripps Research, led by Professor Xiang-Lei Yang, PhD, investigated a common molecular thread among CMT-linked genes: the family of aminoacyl-tRNA synthetase (aaRS) enzymes. These essential enzymes are present in every cell and initiate protein synthesis by attaching the correct amino acid to its matching transfer RNA (tRNA). Given the central role of aaRS enzymes in protein production, mutations in these proteins are an important area of study for neurodegenerative disorders including CMT.
Previous studies that examined mutated aaRS enzymes in isolation suggested a loss of enzymatic function (aminoacylation loss) for some CMT-associated variants. However, Yang’s team took a different, more physiologically relevant route by studying enzymes within patient cells and by analyzing interactions between mutated and wild-type enzymes in their native cellular environment.
Key findings
Using patient-derived samples and a combination of biochemical and biophysical assays, the investigators found that apparent loss of aminoacylation activity often disappears when mutant enzymes are assessed in the context of other healthy enzymes and the cellular milieu. In patient cells, the levels of charged tRNAs were comparable between affected individuals and unaffected family members, indicating that core aminoacylation function was preserved in that physiological context.
Instead of a loss of enzymatic activity, the team observed a structural change: several disease-linked histidyl-tRNA synthetase (HisRS) variants adopted a more relaxed or open conformation at the dimer interface compared with the compact conformation of healthy HisRS. This extended structure exposes extra surface area that is not present in the normal enzyme, and the researchers propose that this exposed surface likely creates abnormal interactions with other cellular proteins.
Importantly, the degree of structural opening correlated with clinical severity in the families studied. Mutations that produced the largest conformational relaxation were associated with the most severe disease phenotypes, whereas the magnitude of in vitro aminoacylation loss did not predict disease severity. These results argue for a gain-of-function or neomorphic mechanism driven by altered protein conformation rather than a simple loss of canonical enzymatic activity.
Implications for treatment and next steps
These findings shift the mechanistic focus for HisRS-linked CMT from loss of aminoacylation function to structural alteration and aberrant interactions. If disease arises from unwanted protein–protein interactions driven by an open enzyme conformation, therapeutic strategies could aim to stabilize the enzyme in its native compact form, block harmful interactions, or modulate downstream pathways triggered by the altered surface exposure.
Yang and colleagues plan to extend their work to examine how different CMT-causing aaRS mutations relate to one another and to explore common therapeutic strategies that may apply across multiple genetic subtypes of CMT. The team emphasizes that understanding the fundamental molecular and cellular defects in CMT is a critical step toward developing effective therapies.
Clinical context
CMT affects approximately 1 in 2,500 people, and there is currently no cure. By uncovering a unifying structural mechanism in a major protein family linked to the disease, this research opens new avenues for drug discovery that target protein conformation and pathological interactions rather than only attempting to restore canonical enzymatic activity.
Study details
The peer-reviewed study, published in PNAS, is titled “CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.” Authors include David Blocquel, Litao Sun, Zaneta Matuszek, Sheng Li, Thomas Weber, Bernhard Kuhle, Grace Kooi, Na Wei, Jonathan Baets, Tao Pan, Paul Schimmel, and Xiang-Lei Yang. Funding was provided in part by the National Institutes of Health (Grant R01 GM088278) and a fellowship from the National Foundation for Cancer Research.