Drosophila Models for Charcot–Marie–Tooth Neuropathy Related to Aminoacyl-tRNA Synthetases

Abstract

Aminoacyl-tRNA synthetases (aaRS) represent the largest cluster of proteins implicated in Charcot–Marie–Tooth neuropathy (CMT), the most common neuromuscular disorder. Dominant mutations in six aaRS cause different axonal CMT subtypes with common clinical characteristics, including progressive distal muscle weakness and wasting, impaired sensory modalities, gait problems and skeletal deformities. These clinical manifestations are caused by “dying back” axonal degeneration of the longest peripheral sensory and motor neurons. Surprisingly, loss of aminoacylation activity is not a prerequisite for CMT to occur, suggesting a gain-of-function disease mechanism. Here, we present the Drosophila melanogaster disease models that have been developed to understand the molecular pathway(s) underlying GARS1- and YARS1-associated CMT etiology. Expression of dominant CMT mutations in these aaRSs induced comparable neurodegenerative phenotypes, both in larvae and adult animals. Interestingly, recent data suggests that shared molecular pathways, such as dysregulation of global protein synthesis, might play a role in disease pathology. In addition, it has been demonstrated that the important function of nuclear YARS1 in transcriptional regulation and the binding properties of mutant GARS1 are also conserved and can be studied in D. melanogaster in the context of CMT. Taken together, the fly has emerged as a faithful companion model for cellular and molecular studies of aaRS-CMT that also enables in vivo investigation of candidate CMT drugs.

An asymmetric structure of bacterial TrpRS supports the half-of-the-sites catalytic mechanism and facilitates antimicrobial screening

“…Notably, it has been proven that most CMT mutations of AARSs are related to the weakened dimer ( 61 , 64 ). Dimer disassociation likely plays an important role in both the loss-of-function and gain-of-function mechanisms of the development of AARS-associated CMT diseases ( 61 , 65 ). In this study, gel filtration assays revealed that even wild-type Ec TrpRS has the potential to dissociate from dimer to monomer, especially in the apo state.…”

Case Report: A new case of YARS1-associated autosomal recessive disorder with compound heterozygous and concurrent 47, XXY

“…This interaction triggers a transcriptional response that subsequently alters neurodevelopment, dendrite morphogenesis, and glucose metabolism ( 12 ). It is noteworthy that the manifestations of ARS-associated CMT are primarily attributed to length-dependent axonal degeneration rather than demyelination ( 13 ). In the case of YARS1-associated CMT, upper extremity weakness and atrophy, along with hyperreflexia, have been reported ( 12 ).…”

Aminoacyl‐tRNA synthetase – a molecular multitasker

“…This implied that point mutations, such as E71G and L129P, cause the variations resulting in a loss of function. 7,110 Few studies have reported the lowering of aminoacylation activity of GlyRS by the nine CMT-causing mutations, which are G526R, G240R, G598A, P244L, A57V, D146N, I280F, H418R, S211F, and the gars1Δ yeast strain is not saved by these variants. 104,111 The second AaRS linked to CMT is TyrRS; it was discovered to have a mutant residue (G41R) in the ATP recognition area, which might affect the binding of ATP with TyrRS, whereas charge reversal was observed in the mutant (E196K), which may alter the structural integrity of TyrRS.…”

“…In the Drosophila model of the GlyRS‐induced CMT2D, neuronal abnormalities, such as axonal and dendritic defects in mushroom body ˠ neurons, along with severe dendritic defects in olfactory projections, were detected. This implied that point mutations, such as E71G and L129P, cause the variations resulting in a loss of function 7,110 . Few studies have reported the lowering of aminoacylation activity of GlyRS by the nine CMT‐causing mutations, which are G526R, G240R, G598A, P244L, A57V, D146N, I280F, H418R, S211F, and the gars1Δ yeast strain is not saved by these variants 104,111 …”