Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease

Bogdanik, Laurent; Sleigh, James N.; Tian, Cong; Samuels, Mark E.; Bedard, Karen; Seburn, Kevin L.; Burgess, Robert W.

doi:10.1242/dmm.010942

Cited by 44 publications

(50 citation statements)

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“…This raises intriguing questions regarding the endogenous LRSAM1 targets and seems to link processes of mitochondrial dynamics and autophagy. Animal models have proven that LRSAM1 mutations cause neurological disease in mouse and zebrafish 1, 8. In this respect, it is interesting to note that lrsam1 −/− mice when challenged with acrylamide showed poor coordination and tremor 8.…”

Section: Discussionmentioning

confidence: 99%

“…Animal models have proven that LRSAM1 mutations cause neurological disease in mouse and zebrafish 1, 8. In this respect, it is interesting to note that lrsam1 −/− mice when challenged with acrylamide showed poor coordination and tremor 8. Additionally, LRSAM1 has been linked to Huntington's disease (HD), suggesting that LRSAM1 also plays a role in CNS neurons 9.…”

Section: Discussionmentioning

confidence: 99%

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A LRSAM1 mutation links Charcot–Marie–Tooth type 2 to Parkinson's disease

Aerts

Weterman

Quadri

et al. 2015

Ann Clin Transl Neurol

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LRSAM1 mutations have been found in recessive and dominant forms of Charcot–Marie–Tooth disease. Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset. We speculate that this late‐onset parkinsonism is part of the LRSAM1 phenotype, thus associating a hitherto peripheral nerve disease with a central nervous system phenotype. How the mutated Lrsam1 protein, which normally has E3 ubiquitin ligase activity and is expressed in the nervous system, impacts on substantia nigra neurons is unclear.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A LRSAM1 mutation links Charcot–Marie–Tooth type 2 to Parkinson's disease

Aerts

Weterman

Quadri

et al. 2015

Ann Clin Transl Neurol

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“…Sensory and motor behavior were assessed as previously described (12,(70)(71)(72)(73)(74), with modifications as listed in SI Appendix, SI Materials and Methods.…”

Section: Methodsmentioning

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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“…Human leucine-rich repeat and sterile alpha motif containing 1 (LRSAM1) is classified as a typical RING-finger E3 ubiquitin ligase. The full-length cDNA of LRSAM1 predicts six N-terminal leucinerich repeat (LRR) domains, two coiled-coil (CC) domains, one sterile-alpha motif (SAM), two Pro-(Ser/Thr)-Ala-Pro (PTAP) tetrapeptide motifs and a C-terminal C3HC4-type RING-finger domain [3,4].…”

Section: Introductionmentioning

confidence: 99%