Neuropathy-associated histidyl-tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish

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dc.contributor.authorMullen, Patrick
dc.contributor.authorAbbott, Jamie A.
dc.contributor.authorWellman, Theresa
dc.contributor.authorAktar, Mahafuza
dc.contributor.authorFjeld, Christian
dc.contributor.authorDemeler, Borries
dc.contributor.authorEbert, Alicia M.
dc.contributor.authorFrancklyn, Christopher S.
dc.date.accessioned2022-10-25T17:15:00Z
dc.date.available2022-10-25T17:15:00Z
dc.date.issued2021
dc.descriptionAccepted author manuscripten_US
dc.description.abstractCharcot-Marie-Tooth disease (CMT) encompasses a set of genetically and clinically heterogeneous neuropathies characterized by length dependent dysfunction of the peripheral nervous system. Mutations in over 80 diverse genes are associated with CMT, and aminoacyl-tRNA synthetases (ARS) constitute a large gene family implicated in the disease. Despite considerable efforts to elucidate the mechanistic link between ARS mutations and the CMT phenotype, the molecular basis of the pathology is unknown. In this work, we investigated the impact of three CMT-associated substitutions (V155G, Y330C, R137Q) in the cytoplasmic histidyl-tRNA synthetase (HARS1) on neurite outgrowth and peripheral nervous system development. The model systems for this work included a nerve growth factor stimulated neurite outgrowth model in rat pheochromocytoma cells (PC12), and a zebrafish line with GFP/RFP reporters of sensory and motor neuron development. Expression of CMT-HARS1 mutations led to attenuation of protein synthesis and increased phosphorylation of eIF2α in PC12 cells and was accompanied by impaired neurite and axon outgrowth in both models. Notably, these effects were phenocopied by histidinol, a histidyl-tRNA synthetase inhibitor, and cycloheximide, a protein synthesis inhibitor. The mutant proteins also formed heterodimers with wild-type HARS1, raising the possibility that CMT-HARS1 mutations cause disease through a dominant negative mechanism. Overall, these findings support the hypothesis that CMT-HARS1 alleles exert their toxic effect in a neuronal context, and lead to dysregulated protein synthesis. These studies demonstrate the value of zebrafish as a model for studying mutant alleles associated with CMT, and for characterizing the processes that lead to peripheral nervous system dysfunction.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationMullen, P., Abbott, J. A., Wellman, T., Aktar, M., Fjeld, C., Demeler, B., Ebert, A. M., & Francklyn, C. S. (2021). Neuropathy-associated histidyl-tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish. The FEBS Journal, 288(1), 142-159. https://doi.org/10.1111/febs.15449 https://doi.org/10.1111/febs.15449en_US
dc.identifier.urihttps://hdl.handle.net/10133/6360
dc.language.isoen_CAen_US
dc.publisherWileyen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUniversity of Vermonten_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.1111/febs.15449en_US
dc.subjectPeripheral neuropathyen_US
dc.subjectProtein synthesisen_US
dc.subjecttRNAen_US
dc.subjectZebrafish
dc.subject.lcshAminoacyl-tRNA
dc.subject.lcshTransfer RNA
dc.subject.lcshCharcot-Marie-Tooth disease
dc.subject.lcshNeuropathy
dc.subject.lcshProteins--Synthesis
dc.titleNeuropathy-associated histidyl-tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafishen_US
dc.typeArticleen_US
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