Investigating the cause of the cell-type specificity in Charcot-Marie-Tooth disease type 2D


Translational Research

Poster Number: T401


Jiaxin Li, Jackson Laboratory

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited diseases causing damage to the peripheral nervous system. CMT type 2D is caused by dominant mutations in GARS1, which encodes glycyl-tRNA synthetase (GARS), the protein that charges glycine onto tRNAGly . In CMT2D, the integrated stress response (ISR) is activated by the kinase GCN2, which contributes to axon degeneration in motor neurons. The activation of ISR suppresses cap-dependent protein translation and induces transcription factor (ATF4), which upregulates downstream stress-response genes. GARS1 is ubiquitously expressed across tissues, consistent with its essential, non-redundant function of tRNA charging, but GARS1 mutations only induce ISR activation and axon degeneration in alpha motor neurons and a subset of sensory neurons. In this study, we aim to determine the underlying causes of the cell type-specificity in CMT2D by comparing gene expression of affected neurons and unaffected cell types in both mouse models and human induced pluripotent stem cells (hiPSCs)-derived neurons. We identified key factors in the disease mechanism that demonstrate unique expression patterns common to the affected cell types. We also discovered ISR activation in CMT2D skeletal muscle, a cell-type that shares the same gene expression pattern. Pilot data showing the correlation between expression profile and disease phenotype in different cell types will be presented. Further research will assess the causal relationship between these identified factors and CTM2D. This study will allow us to gain a better understanding of the cell-type specificity and pathogenesis of CMT2D, and provide a foundation for developing novel treatments for CMT2D and other aaRS-associated CMT.