Abstract
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease’s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.
Highlights
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-MarieTooth neuropathy (CMT2D)
We searched in databases for potential interaction partners of GlyRS involved in axonal transport and found histone deacetylase 6 (HDAC6) as a candidate[33]
To understand whether the effect of P234KY is shared by other CMT type 2D (CMT2D)-associated mutations, we transfected the mouse motor neuron cell line NSC-34 with V5-tagged GlyRSCMT2D constructs of nine different human mutations along with the C157R and P234KY mutations found in CMT2D mouse models[14, 34]
Summary
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-MarieTooth neuropathy (CMT2D). An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Genetic deletion of one Gars allele in mice to reduce GlyRS expression to 50% level does not yield any phenotype[14]; transgenic overexpression of wild-type (WT) GlyRS cannot rescue phenotypes in mouse and Drosophila models of CMT2D15, 16 These results indicate that CMT2D is not caused by a simple loss of WT protein function, and instead arises from abnormal activities of mutant GlyRSCMT2D. The removal of the modification is catalyzed by histone deacetylase 6 (HDAC6)[29, 30], whose inhibition has been shown to increase α-tubulin acetylation[31], rescue axonal transport defects[32], and provide benefits in animal models of neurodegenerative diseases, including a subtype of CMT2
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