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Título

Mutations in TrkA Causing Congenital Insensitivity to Pain with Anhidrosis (CIPA) Induce Misfolding, Aggregation, and Mutation-dependent Neurodegeneration by Dysfunction of the Autophagic Flux

AutorFranco, María Luisa; Melero, Cristina; Sarasola, Esther; Acebo, Paloma; Luque, Alfonso; Calatayud-Baselga, Isabel; García-Barcina, María; Vilar, Marçal
Palabras claveER quality control
TRK1-transforming tyrosine kinase protein (Trk-A)
Autophagic flux
Autophagy
Congenital insensitivity to pain with anhidrosis
Neurodegeneration
Protein aggregation
Fecha de publicación7-oct-2016
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJournal of Biological Chemistry 291(41):21363-21374 (2016)
ResumenCongenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain, and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager. We found that TrkA mutations induce misfolding, retention in the endoplasmic reticulum (ER), and aggregation in a mutation-dependent manner. The distinct mutations are degraded with a different kinetics by different ER quality control mechanisms; although C300stop is rapidly disposed by autophagy, Δ736 degradation is sensitive to the proteasome and to autophagy inhibitors, and L213P is a long-lived protein refractory to degradation. In addition L213P enhances the formation of autophagic vesicles triggering an increase in the autophagic flux with deleterious consequences. Mouse cortical neurons expressing L213P showed the accumulation of LC3-GFP positive puncta and dystrophic neurites. Our data suggest that TrkA misfolding and aggregation induced by some CIPA mutations disrupt the autophagy homeostasis causing neurodegeneration. We propose that distinct disease-causing mutations of TrkA generate different levels of cell toxicity, which may provide an explanation of the variable intellectual disability observed in CIPA patients.
Descripción13 páginas, 9 figuras. This research was originally published in Journal of Biological Chemistry. Franco M.L., Melero C., Sarasola E., Acebo P., Luque A., Calatayud-Baselga I., Garcia-Barcina M.,Vilar M. (2016). Mutations in TrkA causing congenital insensitivity to pain with anhidrosis (CIPA) induce misfolding, aggregation and mutation-dependent neurodegeneration by dysfunction of the autophagic flux. J Biol Chem 291(41): 21363-74. © the American Society for Biochemistry and Molecular Biology.
Versión del editorhttp://dx.doi.org/10.1074/jbc.M116.722587
URIhttp://hdl.handle.net/10261/140931
DOI10.1074/jbc.M116.722587
ISSN0021-9258
E-ISSN1083-351X
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