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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein

In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein

Published on: January 2, 2015

La mutación hipomórfica autosómica dominante de la PCV perjudica la desagregación del PHF-tau

Nabil F Darwich¹, Jessica M Phan¹, Boram Kim¹

¹Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, USA.

Science (New York, N.Y.)

|October 2, 2020

Resumen

Una mutación genética en la proteína que contiene valosina (VCP) altera la desagregación de tau, lo que lleva a enredos neurofibrilares y demencia. Esta mutación de VCP ofrece un objetivo terapéutico potencial para la enfermedad de Alzheimer y las tauopatías relacionadas.

Área de la Ciencia:

La neurociencia
La genética
La bioquímica

Sus antecedentes:

La patogénesis de la enfermedad de Alzheimer (EA) implica la acumulación de proteína tau patológica en ovillos neurofibrilares.
La proteína que contiene valosina (VCP) está implicada en la homeostasis de las proteínas y tiene funciones potenciales en enfermedades neurodegenerativas.

Objetivo del estudio:

Investigar el papel de una mutación específica del VCP (p.Asp395Gly) en la demencia y la degeneración neurofibrilar.
Determinar si el VCP posee actividad de desagregación tau y si la mutación afecta esta función.

Principales métodos:

Examen neuropatológico de los casos de demencia con la mutación p.Asp395Gly VCP.
Ensayos in vitro para evaluar la actividad de la desagregación tau del VCP y el efecto de la mutación p.Asp395Gly.
Modelos de ratón con una mutación de p.Asp395Gly en VCP para estudiar la agregación de tau después de la microinyección de tau.

Principales resultados:

La mutación p.Asp395Gly VCP se asoció con demencia, vacuolas neuronales y ovillos neurofibrilares.
El VCP demostró actividad de desagregación tau in vitro, que se vio significativamente afectada por la mutación p.Asp395Gly.
Los ratones con la mutación p.Asp395Gly VCP mostraron una mayor agregación de tau tras la microinyección patológica de tau en comparación con los ratones de tipo salvaje.

Conclusiones:

La mutación p.Asp395Gly VCP es una causa genética autosómica dominante de la degeneración neurofibrilar.
El deterioro de la desagregación tau debido a la mutación VCP contribuye a la neurodegeneración.
El VCP representa un objetivo terapéutico potencial para la enfermedad de Alzheimer y otras tauopatías.

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