Interplay between Phase Separation and Amyloid Formation of TDP-43 C-terminal domain

Date

Jul 1, 2026

Time

11:00 AM - 12:00 PM

Speaker

Jennifer Lee

Affiliation

National Heart, Blood, and Lung Institute, USA

Series

Physics of Life Seminar

Language

en

Main Topic

Physik

Host

Ellen Adams

Description

We are pleased to announce a new PoL Seminar by Jennifer Lee from the National Heart, Blood, and Lung Institute, USA

When?  Wednesday, 1. July 2026, 11:00 am
Where? CRTD auditorium left

Abstract:

Liquid-liquid phase-separation (LLPS) is a physical phenomenon in which biomolecules spontaneously form metastable, concentrated droplet phases. Understanding the link between LLPS and the disease-related process of amyloid formation has attracted significant interest. Here, we investigated the relationship between LLPS and aggregation of the C-terminal domain (CTD) of the transactive response DNA binding protein of 43 kD (TDP-43). TDP-43CTD is found in cytoplasmic inclusions associated with amyotrophic lateral sclerosis and frontotemporal lobar dementia. A prevailing hypothesis suggests that a liquid-to-solid transition occurs during TDP-43CTD droplet maturation, involving formation of β-sheet–rich, amyloid-like pathological aggregates. To evaluate how protein secondary structure evolves temporally and spatially within individual condensates, we employed label-free Raman spectral imaging to assess kinetics and spatial heterogeneity of β-sheet development at the individual droplet level. To obtain site-specific information, we substituted a Raman-active, environmentally-sensitive unnatural amino acid, 4-ethynylphenylalanine, at various aromatic sites via amber codon suppression. Despite the development of β-sheet structure, conformers within aged droplets are distinguishable from fibrillar aggregates as shifts in the alkyne band indicate local environmental differences between the two forms. Interestingly, both aged droplets and fibrillar aggregates exhibited distinctive spectral features in distal N- and C-terminal sites outside the structured amyloid core. Importantly, our results reveal fibril polymorphism in the C-terminal region. The coexistence of solidified droplets and amyloid fibrils indicates that these structures represent distinct pathways. While droplets are amyloid-like, amyloid fibrils can form independently of droplets, challenging the paradigm that phase separation is an obligate step in amyloid formation.

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Everybody is very welcome. Don’t miss a great opportunity to join the seminar!

Please note: This seminar is going to take place in person at CRTD and will not be streamed via Zoom.

Links

• See this event on the Physics of Life website

Last modified: Jul 1, 2026, 7:35:27 AM