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La prolyl isomerase Pin1 regula el procesamiento de proteínas precursoras de amiloide y la producción de beta
Lucia Pastorino1, Anyang Sun, Pei-Jung Lu
1Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nature
|March 24, 2006
Resumen
La Pin1 prolyl isomerase regula el procesamiento de la proteína precursora amiloide (APP) y la producción de beta amiloide (Abeta). La desregulación de Pin1 aumenta el Abeta42 tóxico, vinculando las patologías tau y Abeta en la enfermedad de Alzheimer.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- La enfermedad de Alzheimer (EA) se caracteriza por enredos neurofibrilares (tau) y placas amiloides (amiloide-beta, Abeta).
- La relación entre tau y Abeta en la patogénesis de la EA no se entiende completamente.
- Pin1, una isomerasa prolyl, regula la conformación de las proteínas y está implicada en la patogénesis de la EA.
Objetivo del estudio:
- Para investigar el papel de Pin1 en el procesamiento de la proteína precursora amiloide (APP) y la producción de Abeta.
- Para dilucidar el mecanismo por el cual Pin1 influye en la conformación del dominio intracelular de APP (AICD).
- Para determinar la importancia patológica de la regulación mediada por Pin1 en modelos de la enfermedad de Alzheimer.
Principales métodos:
- Espectroscopia de Resonancia Magnética Nuclear (RMN) para visualizar las conformaciones del AICD.
- Experimentos de cultivo celular para evaluar la secreción de Abeta.
- Modelos de ratón con knockout Pin1 y / o mutante APP sobreexpresión.
- Inmunohistoquímica para localizar Abeta42 en el cerebro.
Principales resultados:
- Pin1 se une al motivo de Thr668-Pro fosforilado en APP, acelerando la isomerización de AICD más de 1.000 veces.
- La sobreexpresión de Pin1 reduce la secreción de Abeta, mientras que el nocaut de Pin1 la aumenta.
- El knockout de Pin1 en ratones eleva el procesamiento de APP amiloidogénico y el Abeta42 insoluble de manera dependiente de la edad.
Conclusiones:
- La isomerización de prolyl catalizada por pin1 es un nuevo mecanismo regulador para el procesamiento de APP y la producción de Abeta.
- La desregulación de la actividad de Pin1 puede vincular las patologías tau y Abeta en la enfermedad de Alzheimer.
- Dirigirse a Pin1 ofrece una estrategia terapéutica potencial para la enfermedad de Alzheimer.
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