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Liquid-Liquid Phase Separation Enhances TDP-43 LCD Aggregation but Delays Seeded Aggregation
Donya Pakravan1,2, Emiel Michiels3, Anna Bratek-Skicki4
1Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, 3000 Leuven, Belgium.
Biomolecules
|April 30, 2021
Summary
Liquid-liquid phase separation (LLPS) promotes TAR DNA-binding protein (TDP-43) self-aggregation but hinders seeded aggregation. RNA concentration influences this interplay, impacting neurodegenerative disease mechanisms.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Aggregates of TAR DNA-binding protein (TDP-43) are key pathological markers in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS).
- The precise molecular events initiating TDP-43 aggregation remain incompletely understood, despite its established role in disease pathogenesis.
Purpose of the Study:
- To investigate the influence of liquid-liquid phase separation (LLPS) on the self-aggregation and seeded aggregation of the TDP-43 low-complexity domain (LCD).
- To explore how physicochemical conditions and RNA concentration modulate TDP-43 aggregation kinetics and phase separation behavior.
Main Methods:
- Systematic variation of physicochemical conditions to induce and observe liquid-liquid phase separation (LLPS) of TDP-43 LCD and its aggregation.
- Utilized the Hofmeister series of buffers to analyze the impact of ionic strength and specific ions on phase separation and aggregation.
- Investigated the effect of varying RNA concentrations on the interplay between LLPS and TDP-43 aggregation.
Main Results:
- Liquid-liquid phase separation (LLPS) was found to promote spontaneous self-aggregation of TDP-43 LCD.
- Seeded aggregation of TDP-43 LCD was less efficient under phase-separating conditions compared to non-phase-separating conditions.
- Hydrophobic interactions were confirmed to be dominant over electrostatic forces in stabilizing TDP-43 aggregation under tested conditions.
- RNA exhibited a 'reentrant' effect, enhancing the cooperativity between LLPS and aggregation most effectively at intermediate concentrations.
Conclusions:
- Conditions favoring LLPS enhance the subsequent aggregation of TDP-43 LCD, but with a complex concentration dependence.
- LLPS negatively impacts the kinetics of seeded aggregation, suggesting a potential mechanism for altered proteinopathy progression.
- The findings highlight the critical role of phase separation and RNA in modulating TDP-43 aggregation pathways relevant to neurodegeneration.
