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.
Highlights
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Aminoacyl-tRNA synthetases are the most represented protein family associated with Charcot–Marie–Tooth neuropathy (CMT) to date, with dominant mutations described in six genes (Figure 1, Table 1): Genes 2021, 12, 1519
Similar conclusions were made for GARS1 using genetic complementation experiments performed in dorsolateral glomerulus 1 (DL1) projection neurons [65]
Summary
Peripheral nervous system is the anatomical part of the nervous system connecting brain and spinal cord to the other organs in the body, innervating muscles as well as providing sensory input [1]. The initial dichotomous classification of CMT was expanded to include an intermediate disease type (I-CMT) recognized in families where nerve conduction velocities in individual patients range between 25–45 m/s. These patients show a combination of loss of myelination, progressive dying back of the axons coupled with onion bulb formation and presence of regenerating fibers [14]. There is no obvious unifying overarching theme explaining the mechanistic involvement of the various types of proteins in the disease process altogether It is unclear how essential and ubiquitous proteins could cause a very specific degeneration restricted to the peripheral nerves. A better understanding of the pathophysiological consequences of genetic abnormalities remains crucial to develop efficient therapies for the patients
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