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Memorias de investigación
Ponencias en congresos:
Mechanism of demyelination by connexin-43 mutations associated with oculodentodigital dysplasia
Año:2015
Áreas de investigación
  • Ciencias naturales y ciencias de la salud
Datos
Descripción
A wide variety of devastating neurological diseases result from the genetic or autoimmune disruption of glial mechanisms that support the integrity of myelin at CNS. In that regards, it is noteworthy that certain autosomal dominant mutations in the gene GJA1 encoding gap junction protein connexin-43 (Cx43) cause oculodentodigital dysplasia (ODDD) with spastic paraplegia. However, it is not known how these mutants expressed within astrocytes can produce demyelination. We postulate that the disease-related mutations would interfere with the intercellular communication astrocyte-astrocyte and astrocyte-oligodendrocyte, which are mainly mediated respectively by homotypic intercellular channels of Cx43 and heterotypic channels of Cx43 with oligodendrocyte Cx47. This glial network is specialized, among other functions, in the long-distance siphoning of K+ ions released into the internodal periaxonal space of myelin during the ?saltatory conduction? of action potentials. Here we report a three-generation family with the c.253G>A heterozygous mutation (p.V85M) in which all carriers present an ODDD phenotype with spastic paraplegia. Functional assay in Xenopus oocytes and N2A cells revealed that mutation V85M impairs the formation of homotypic intercellular channels by itself and that under the heterozygous condition of patients the mutated protein exerts a potent dominant inhibition over the channel-forming ability of wild-type Cx43. Similarly, cultured human astrocytes that normally form an extensive cellular network interconnected by endogenous Cx43 channels uncoupled when they were transfected with the V85M mutant. Coexpression of mutant V85M with wild-type Cx43 reduced but not abolished the coupling mediated by heterotypic Cx43-Cx47 channels and their rectifying properties were preserved. The results suggest that demyelination of patients might be primary due to disruption of intercellular astrocyte-astrocyte communication, and therefore K+ siphoning is blocked, axonal saltatory conduction ceases and myelin is destroyed.
Internacional
Si
Nombre congreso
5th Spanish Ion Channel Network Meeting (RECI): Present and Future Research in Ion Channel Research
Tipo de participación
970
Lugar del congreso
BARCELONA
Revisores
Si
ISBN o ISSN
0000-0000-00
DOI
Fecha inicio congreso
04/10/2015
Fecha fin congreso
06/10/2015
Desde la página
60
Hasta la página
60
Título de las actas
ABSTRACTS BOOK RECI
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Participantes
  • Autor: Daniel Gonzalez Nieto (UPM)
  • Autor: LC BARRIO
  • Autor: M ARDAIZ
  • Autor: A ESCUDERO
  • Autor: P MARTINEZ MONTERO
  • Autor: J MOLANO
  • Autor: J GARCIA DE YEBENES
  • Autor: C PAINO
  • Autor: MJ SOBRIDO
  • Autor: B QUINTANS
Grupos de investigación, Departamentos, Centros e Institutos de I+D+i relacionados
  • Creador: Grupo de Investigación: Tecnologías para Ciencias de la Salud
  • Centro o Instituto I+D+i: Centro de tecnología Biomédica CTB
  • Departamento: Tecnología Fotónica y Bioingeniería
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