Tomomi Takahashi , Takashi Nonaka , Reiko Ohtani , Masato Hasegawa , Yukiko Hori , Taisuke Tomita , Rei Kurita
{"title":"Hindering tau fibrillization by disrupting transient precursor clusters","authors":"Tomomi Takahashi , Takashi Nonaka , Reiko Ohtani , Masato Hasegawa , Yukiko Hori , Taisuke Tomita , Rei Kurita","doi":"10.1016/j.neures.2025.104968","DOIUrl":null,"url":null,"abstract":"<div><div>Tau protein, a central player in Alzheimer’s disease (AD), exhibits cytotoxicity upon fibril formation. Understanding the early stages of tau fibrillization is therefore critical for the development of effective therapeutics. Previous work [Rasmussen. et. al, J. Mol. Biol., 2023] reported the rapid formation of Thioflavin T (ThT)-inactive clusters upon mixing tau with anionic polymers, yet the functional role of these clusters remained unclear. Here, we demonstrate that these transient clusters act as obligatory precursors in the fibrillization pathway. Using small-angle X-ray scattering (SAXS) and ThT fluorescence, we show that disrupting the clusters via NaCl addition hinders fibril formation, highlighting their reversible and targetable nature. This behavior is analogous to polymer crystallization, in which disordered chains undergo structural ordering through intermediate precursor states. We propose that similar physical principles underlie the aggregation of other intrinsically disordered proteins such as <em>α</em>-synuclein.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"220 ","pages":"Article 104968"},"PeriodicalIF":2.3000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0168010225001518","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Tau protein, a central player in Alzheimer’s disease (AD), exhibits cytotoxicity upon fibril formation. Understanding the early stages of tau fibrillization is therefore critical for the development of effective therapeutics. Previous work [Rasmussen. et. al, J. Mol. Biol., 2023] reported the rapid formation of Thioflavin T (ThT)-inactive clusters upon mixing tau with anionic polymers, yet the functional role of these clusters remained unclear. Here, we demonstrate that these transient clusters act as obligatory precursors in the fibrillization pathway. Using small-angle X-ray scattering (SAXS) and ThT fluorescence, we show that disrupting the clusters via NaCl addition hinders fibril formation, highlighting their reversible and targetable nature. This behavior is analogous to polymer crystallization, in which disordered chains undergo structural ordering through intermediate precursor states. We propose that similar physical principles underlie the aggregation of other intrinsically disordered proteins such as α-synuclein.
期刊介绍:
The international journal publishing original full-length research articles, short communications, technical notes, and reviews on all aspects of neuroscience
Neuroscience Research is an international journal for high quality articles in all branches of neuroscience, from the molecular to the behavioral levels. The journal is published in collaboration with the Japan Neuroscience Society and is open to all contributors in the world.