RESUMEN
Tau plays a major role in Alzheimer's disease (AD) and several other neurodegenerative diseases. Tau undergoing liquid-liquid phase separation (LLPS) performs specific physiological functions, induces pathological processes, and contributes to neurodegeneration. Regulating Tau phase separation helps maintain physiological functions of Tau and inhibits pathological aggregation. Here, we show that the 14-3-3 zeta isoform (14-3-3ζ) participates in Tau LLPS. 14-3-3ζ can undergo co-phase separation with WT Tau, participate in and stabilize Tau droplets, and inhibit Tau droplet-driven tubulin assembly. On the other hand, 14-3-3ζ disrupts the LLPS of phosphorylated and glycated Tau, thereby inhibiting the amyloid aggregation initiated by LLPS.
Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Humanos , Proteínas tau/metabolismo , Proteínas 14-3-3/metabolismo , Enfermedad de Alzheimer/patología , Isoformas de ProteínasRESUMEN
Liquid-liquid phase separation (LLPS), a type of phase transition that is important in organisms, is a unique means of forming biomolecular condensates. LLPS plays a significant role in transcription, genome organisation, immune response and cell signaling, and its dysregulation may cause neurodegenerative diseases and cancers. Exploring the regulatory mechanism of LLPS contributes to the understanding of the pathogenic mechanism of abnormal phase transition and enables potential therapeutic targets to be proposed. Many factors have been found to regulate LLPS, of which post-translational modification (PTM) is among the most important. PTMs can change the structure, charge, hydrophobicity and other properties of the proteins involved in phase separation and thereby affect the phase transition behaviour. In this review, we discuss LLPS and the regulatory effects of PTMs, RNA and molecular chaperones in a phase separation system. We introduce several common PTMs (including phosphorylation, arginine methylation, arginine citrullination, acetylation, ubiquitination and poly(ADP-ribosyl)ation), highlight recent advances regarding their roles in LLPS and describe the regulatory mechanisms behind these features. This review provides a detailed overview of the field that will help further the understanding of and interventions in LLPS.
RESUMEN
We developed a new method for protein droplet visualization by means of a droplet probe (DroProbe) based on an aggregation-induced emission (AIE) fluorogen. A simple method for viscosity comparison of the protein condensed phase based on the lifetime of the DroProbe was also developed.
RESUMEN
Herein, we have successfully semi-synthesized a TDP-43 prion-like domain with Ser404 phosphorylation. We have demonstrated that Ser404 phosphorylation could accelerate the amyloid aggregation of the TDP-43 prion-like domain and aggravate its cytotoxicity.
Asunto(s)
Proteínas Amiloidogénicas/farmacología , Proteínas de Unión al ADN/farmacología , Fragmentos de Péptidos/farmacología , Proteínas Priónicas/farmacología , Serina/química , Proteínas Amiloidogénicas/síntesis química , Proteínas Amiloidogénicas/metabolismo , Proteínas Amiloidogénicas/toxicidad , Animales , Línea Celular Tumoral , Proteínas de Unión al ADN/síntesis química , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/toxicidad , Ratones , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Fosforilación , Proteínas Priónicas/síntesis química , Proteínas Priónicas/metabolismo , Proteínas Priónicas/toxicidad , Dominios Proteicos , Multimerización de ProteínaRESUMEN
It has been reported that many molecules could inhibit the aggregation of Aß (amyloid-ß) through suppressing either primary nucleation, secondary nucleation, or elongation processes. In order to suppress multiple pathways of Aß aggregation, we screened 23 small molecules and found two types of inhibitors with different inhibiting mechanisms based on chemical kinetics analysis. Trp-glucose conjugates (AS2) could bind with fibril ends while natural products (D3 and D4) could associate with monomers. A cocktail of these two kinds of molecules achieved co-inhibition of various fibrillar species and avoid unwanted interference.