Secondary nucleation revealed in Huntington amyloid fibrils

A team of researchers from Groningen revealed for the first time the dynamics of secondary nucleation using advanced microscopy approaches. Secondary nucleation is the process in which fibres are formed on top of other fibres. By imaging this process at the single particle level using a “touch” microscope, the researchers were able to visualise this dynamic event. The work recently appeared in the Journal of the American Chemical Society.

In order to study the molecular level dynamics of secondary nucleation, the groups of Wouter Roos and Patrick van der Wel focused on the causative agent of Huntington disease. These agents form fibres called amyloids and these can be toxic to the body. The importance of secondary nucleation was already established, however, it remains a poorly understood process. Despite our poor understanding, it may even be that secondary nucleation is the dominant source of rapid amyloid formation. This underlines the importance of the study. Due to the minute dimensions and its fast aggregation, it was always difficult to observe this process. The researchers from Groningen now tackled this problem by using a fast “touch” microscope, a so called High-Speed Atomic Force Microscope. Thereby they were able to follow the aggregation process of amyloid structures in real time.

In the JACS publication, they show for the first time how small amyloid fibrils associated with Huntington’s disease grow into large fibre clusters and how secondary nucleation occurs along the surface of these fibres. These observations can settle a long-lasting debate on the role of secondary nucleation in amyloid formation, and strongly suggests that therapeutic approaches should be geared towards the prevention of secondary nucleation to hinder amyloid formation.

Read more:

Chris van Ewijk, Greeshma Jain, Yari K. Knelissen, Sourav Maity, Patrick C.A. van der Wel and Wouter H. Roos*

Direct observation of secondary nucleation in huntingtin amyloid formation by High-Speed Atomic Force Microscopy

Journal of the American Chemical Society, 2025, Vol. 147, 21973–21984

https://doi.org/10.1021/jacs.5c05571