Modulation of the extent of structural heterogeneity in α-synuclein fibrils by the small molecule thioflavin T

J Biol Chem. 2017 Oct 13;292(41):16891-16903. doi: 10.1074/jbc.M117.795617. Epub 2017 Jul 31.


The transition of intrinsically disordered, monomeric α-synuclein into β-sheet-rich oligomers and fibrils is associated with multiple neurodegenerative diseases. Fibrillar aggregates possessing distinct structures that differ in toxicity have been observed in different pathological phenotypes. Understanding the mechanism of the formation of various fibril polymorphs with differing cytotoxic effects is essential for determining how the aggregation reaction could be modulated to favor nontoxic fibrils over toxic fibrils. In this study, two morphologically different α-synuclein fibrils, one helical and the other ribbon-like, are shown to form together. Surprisingly, a widely used small molecule for probing aggregation reactions, thioflavin T (ThT), was found to tune the structural heterogeneity found in the fibrils. The ribbon-like fibrils formed in the presence of ThT were found to have a longer structural core than the helical fibrils formed in the absence of ThT. The ribbon-like fibrils are also more toxic to cells. By facilitating the formation of ribbon-like fibrils over helical fibrils, ThT reduced the extent of fibril polymorphism. This study highlights the role of a small molecule such as ThT in selectively favoring the formation of a specific type of fibril by binding to aggregates formed early on one of multiple pathways, thereby altering the structural core and external morphology of the fibrils formed.

Keywords: alpha-synuclein (α-synuclein); atomic force microscopy (AFM); fibril heterogeneity; hydrogen exchange mass spectrometry; neurodegenerative disease; thioflavin T; toxicity.

MeSH terms

  • Benzothiazoles
  • Humans
  • Multiprotein Complexes / chemistry*
  • Protein Aggregation, Pathological*
  • Protein Multimerization*
  • Thiazoles / chemistry*
  • alpha-Synuclein / chemistry*


  • Benzothiazoles
  • Multiprotein Complexes
  • SNCA protein, human
  • Thiazoles
  • alpha-Synuclein
  • thioflavin T