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A Scalable, Cell-Based Method for the Functional Assessment of Ube3a Variants
Published on: October 10, 2022
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Una mutación relacionada con el autismo desactiva el control de la fosforilación de UBE3A
Jason J Yi1, Janet Berrios2, Jason M Newbern3
1Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, The University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, NC 27599, USA.
Cell
|August 11, 2015
Resumen
La proteína quinasa A (PKA) regula el UBE3A, un gen importante para el desarrollo del cerebro. Una mutación relacionada con el autismo interrumpe esta regulación, lo que lleva a una actividad excesiva de UBE3A y a una posible disfunción sináptica.
Área de la Ciencia:
- La neurociencia
- La genética
- La bioquímica
Sus antecedentes:
- La eliminación de UBE3A causa el síndrome de Angelman (SA), y su duplicación / triplicación está relacionada con el autismo.
- La regulación adecuada de la actividad de la ubiquitina ligasa UBE3A es crucial para el desarrollo normal del cerebro.
Objetivo del estudio:
- Investigar la regulación en sentido ascendente de la actividad UBE3A.
- Determinar el impacto funcional de una mutación relacionada con el autismo en la fosforilación y actividad de UBE3A.
Principales métodos:
- Ensayos de quinasa in vitro para evaluar la fosforilación de UBE3A por el PKA.
- Ensayos de actividad enzimática utilizando UBE3A y sus sustratos.
- Análisis de células derivadas de pacientes y tejido cerebral para evaluar la actividad de UBE3A y la morfología de la columna dendrítica.
Principales resultados:
- La proteína quinasa A (PKA) fosforila UBE3A en el residuo T485, inhibiendo su actividad ligasa.
- Una mutación de novo relacionada con el autismo en T485 interrumpe la inhibición mediada por PKA, lo que lleva a una mayor actividad de UBE3A.
- El aumento de la actividad de UBE3A resulta en un aumento de la rotación del sustrato y en un desarrollo excesivo de la columna dendrítica en el tejido cerebral.
Conclusiones:
- PKA es un regulador aguas arriba de UBE3A, controlando su actividad a través de la fosforilación en T485.
- La alteración de este sitio de fosforilación por una mutación relacionada con el autismo conduce a una actividad excesiva de UBE3A.
- La actividad excesiva de UBE3A y la posterior disfunción sináptica están implicadas en la patogénesis del autismo.
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