Dominant, toxic gain-of-function mutations in<i>gars</i>lead to non-cell autonomous neuropathology

Grice, Stuart J.; Sleigh, James N.; Motley, William W.; Liu, Ji‐Long; Burgess, Robert W.; Talbot, Kevin; Cader, M Z

doi:10.1093/hmg/ddv176

Cited by 52 publications

(86 citation statements)

References 56 publications

(72 reference statements)

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“…As neurons and muscle fibres are highly metabolically active, it is rational to hypothesise that the neuromuscular junctions (NMJs) are affected by even minor mitochondrial dysfunction. Recent data showed synaptic maturation abnormalities with specific, progressive NMJ degeneration in Drosophila where ubiquitous mutant gars was expressed [82]. In addition to this, abnormal axonal transport was also suggested as potential disease mechanisms, which have been reported in a range of CMT2 models [60].…”

Section: Synaptic Dysfunctionmentioning

confidence: 84%

The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

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Section: Synaptic Dysfunctionmentioning

confidence: 84%

The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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“…neuropilin 1 (NRP1), which antagonizes VEGF signaling (18). This aberrant binding and noncell autonomous toxicity is contingent upon GlyRS secretion, which occurs from a number of different cell types in culture and is unaffected by neuropathyassociated mutations (17)(18)(19).…”

Section: Significancementioning

confidence: 99%

“…A possible mediator of toxicity was identified when five CMT2D-associated mutations spread along the length of GARS were all shown to induce a similar conformational change in GlyRS, leading to the exposure of surfaces buried in the wild-type protein (16). These neomorphic regions likely facilitate the aberrant accumulation of mutant GlyRS at the neuromuscular junction (NMJ) of a CMT2D Drosophila melanogaster model (17), and nonphysiological extracellular interaction of mutant GlyRS with…”

mentioning

confidence: 99%

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh

Dawes

West

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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135

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Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.aminoacyl-tRNA synthetase | Charcot-Marie-Tooth disease | distal spinal muscular atrophy type V | neuromuscular disease | neurodevelopment C harcot-Marie-Tooth disease (CMT) is a group of genetically diverse peripheral neuropathies that share the main pathological feature of progressive motor and sensory degeneration (1). Although lifespan is usually unaffected, patients display characteristic muscle weakness and wasting predominantly in the extremities, leading to difficulty walking, foot deformities, and reduced dexterity (2). CMT is traditionally divided into type 1/ demyelinating CMTs that display loss of peripheral nerve myelin causing reduced nerve conduction velocity (NCV), type 2/axonal CMTs typified by axon loss with relatively normal NCVs, and intermediate CMTs that share clinical features of CMT1 and -2 (1). Over 80 different genetic loci have been linked to CMT, which is known to affect ∼1/2,500 people, making it the most common group of hereditary neuromuscular disorders (3).Dominant mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS, are causative of CMT type 2D (CMT2D) [Online Mendelian Inheritance in Man (OMIM) 601472], which normally manifests during adolescence and presents with muscle weakness in the extremities (4). The 2D subtype is one of a number of CMTs associated with mutation of an aminoacyl-tRNA synthetase (ARS) gene (5-8). Humans possess 37 ARS proteins, which covalently link amino acids to their partner transfer RNAs (tRNAs), thereby charging and priming the tRNAs for protein synthesis.This housekeeping function of gl...

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“…Orthologs of the Abi protein appear to have important roles in neurogenesis via the regulation of actin dynamics (Proepper et al 2007;Lin et al 2009;Liebau et al 2011). Dominant mutations in GARS cause the distal neuropathy Charcot-MarieTooth disease type 2D, and recent observations suggest that GARS may colocalize with SMN in human cells (Motley et al 2010;Drew et al 2011;Grice et al 2015). Mouse models of SMA exhibit disruptions to ubiquitin homeostasis, and evidence of SMN interactions with proteasomal components, including Psmd1, the mouse ortholog of Drosophila Rpn2 (Aghamaleky Sarvestany et al 2014;Wishart et al 2014).…”

Section: Rna Signatures Of Diseasementioning

confidence: 99%

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

Garcia

Wen

Praveen

et al. 2016

RNA

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Survival motor neuron (SMN) functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing. Here, we used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or gene-specific in Drosophila. Phax and Smn mutants exhibited comparable reductions in snRNAs, and comparison of their transcriptomes uncovered shared sets of RNA processing changes. In contrast, Ars2 mutants displayed only small decreases in snRNA levels, and RNA processing changes in these mutants were generally distinct from those identified in Phax and Smn animals. Instead, RNA processing changes in Ars2 mutants support the known interaction of Ars2 protein with the cap-binding complex, as splicing changes showed a clear bias toward the first intron. Bypassing disruptions in snRNP biogenesis, direct knockdown of spliceosomal proteins caused similar changes in the splicing of snRNP-dependent events. However, these snRNP-dependent events were largely unaltered in three Smn mutants expressing missense mutations that were originally identified in human spinal muscular atrophy (SMA) patients. Hence, findings here clarify the contributions of Phax, Smn, and Ars2 to snRNP biogenesis in Drosophila, and loss-of-function mutants for these proteins reveal differences that help disentangle cause and effect in SMA model flies.

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Dominant, toxic gain-of-function mutations ingarslead to non-cell autonomous neuropathology

Cited by 52 publications

References 56 publications

The role of tRNA synthetases in neurological and neuromuscular disorders

The role of tRNA synthetases in neurological and neuromuscular disorders

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

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