Glycyl-tRNA synthetase mutations are associated to the
Charcot-Marie-Tooth disease type-2D. The GarsP278KY/+ model for
Charcot-Marie-Tooth disease type-2D is known best for its early onset severe neuropathic phenotype with findings including reduced axon size, slow conduction velocities and abnormal neuromuscular junction. Muscle involvement remains largely unexamined. We tested the efficacy of
neurotrophin 3 gene transfer
therapy in two Gars mutants with severe (GarsP278KY/+ ) and milder (GarsΔETAQ/+ ) phenotypes via
intramuscular injection of adeno-associated virus setoype-1, triple tandem
muscle creatine kinase promoter,
neurotrophin 3 (AAV1.tMCK.NT-3) at 1 × 1011 vg dose. In the GarsP278KY/+ mice, the treatment efficacy was assessed at 12 weeks post-injection using rotarod test, electrophysiology and detailed quantitative histopathological studies of the peripheral nervous system including neuromuscular junction and muscle.
Neurotrophin 3 gene transfer
therapy in GarsP278KY/+ mice resulted in significant functional and electrophysiological improvements, supported with increases in myelin thickness and improvements in the denervated status of neuromuscular junctions as well as increases in muscle fibre size along with attenuation of myopathic changes. Improvements in the milder phenotype GarsΔETAQ/+ was less pronounced. Furthermore, oxidative
enzyme histochemistry in muscles from Gars mutants revealed alterations in the content and distribution of oxidative
enzymes with increased expression levels of Pgc1a. Cox1, Cox3 and Atp5d transcripts were significantly decreased suggesting that the muscle phenotype might be related to
mitochondrial dysfunction.
Neurotrophin 3 gene therapy attenuated these abnormalities in the muscle. This study shows that
neurotrophin 3 gene transfer
therapy has disease modifying effect in a mouse model for
Charcot-Marie-Tooth disease type-2D, leading to meaningful improvements in peripheral nerve myelination and neuromuscular junction integrity as well as in a unique myopathic process, associated with
mitochondria dysfunction, all in combination contributing to functional outcome. Based on the multiple
biological effects of this versatile molecule, we predict
neurotrophin 3 has the potential to be beneficial in other
aminoacyl-tRNA synthetase-linked
Charcot-Marie-Tooth disease subtypes.