Aug 2026· Langmuir· Vol 42 34, pp.
24939-24945
· 0 citations· 30 references
Medicine
TL;DR
Using in vitro reconstitution and high-resolution imaging, tRNA is identified as a major inducer of tau aberrant aggregation and captopril effectively inhibits both general and tRNA-induced tau aggregation, positioning CAP as a potential therapeutic candidate.
Abstract
Tau is an intrinsically disordered protein critical to the nervous system, and its aberrant aggregation is a key pathogenic factor in multiple diseases. However, the underlying triggers remain elusive. Here, using in vitro reconstitution and high-resolution imaging, we identify tRNA as a major inducer of tau aberrant aggregation. Mechanistically, tRNA drives the formation of fibrillar aggregates from tau liquid-liquid phase separation (LLPS) condensates via electrostatic interactions, which over time can evolve into pathological aggregates. Moreover, captopril (CAP) effectively inhibits both general and tRNA-induced tau aggregation, positioning CAP as a potential therapeutic candidate. This work offers an avenue for treating aberrant phase separation-induced tau aggregation using small-molecule compounds.
The current literature is summarized and biomolecular condensates are described as key regulators of protein misfolding and aggregation and the importance of the local milieu in determining aggregation outcomes is highlighted.
Emre Pekbilir, Dorothee Dormann· Current Opinion in Structura...· 0 citations
The authors study the impact of DNAJB6b on tau fibril formation, showing that it delays tau aggregation by co-assembling with small tau aggregates and by binding to mature fibrils, reducing their ability to catalyze further fibril growth.
Andreas Carlsson, Emil Axell, Johan Wallerstein et al.· Communications Chemistry· 1 citation· ⚡1
This study shows recruitment begins at a single, structurally well-defined contact site on the fibril surface that is enriched in release-prone hydration water, revealing that water-release-prone hotspots govern the initial steps in templating seeding and can hence be blocked, opening a new path for identifying therape...
Chung-Ta Han, Karen Tsay, Samuel Lobo et al.· bioRxiv· 0 citations
This chapter explores the properties of tau, including its intrinsically disordered nature, isoforms, and post-translational modifications (PTMs), that predispose it to LLPS, and examines how truncation and PTM cross-talk alter the phase behavior and aggregation propensity of tau.
Sangita Rajkhowa, Timir Tripathi· International review of neur...· 0 citations
Key findings linking tau, RNA, and stress granules are cataloged because they could offer novel opportunities to design therapeutic strategies and highlight the importance of RNA stability in tauopathies.
Tristyn N. Garza, J. Abisambra· Cells· 0 citations
It is found that polyubiquitinated tau filaments from Alzheimer disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by cryo-electron microscopy.
Ryohei Watanabe, Benjamin C. Creekmore, Nabil F. Darwich et al.· Nature Structural & Molecula...· 1 citation
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