Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus

Area of Science:

• Biochemistry
• Materials Science
• Neuroscience

Background:

• TDP-43 protein is crucial in forming nuclear bodies and stress granules via phase separation.
• Aberrant TDP-43 aggregation in the nucleus and cytoplasm is linked to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).
• Modulating TDP-43 phase separation and aggregation is a key therapeutic target.

Purpose of the Study:

• To investigate the impact of functionalized graphene quantum dots (GQDs) on TDP-43 phase separation and aggregation.
• To assess the efficacy of halogen atom-doped GQDs in inhibiting TDP-43 pathological condensation in cellular models.

Main Methods:

• Utilized various functionalized GQDs, specifically halogen atom-doped variants (GQDs-Cl, Cl-GQDs-OH).
• Evaluated GQD effects on TDP-43 nuclear bodies and stress granule formation under cellular stress conditions (oxidative, hyperosmotic).
• Analyzed GQD-TDP-43 interactions using mechanistic approaches focusing on hydrophobic and electrostatic interactions.

Main Results:

• Halogen-doped GQDs (GQDs-Cl, Cl-GQDs-OH) successfully penetrated the nuclear envelope.
• These GQDs inhibited TDP-43 nuclear body and stress granule assembly under stress.
• Reduced TDP-43 amyloid aggregates and disease-associated phosphorylation were observed.

Conclusions:

• Functionalized GQDs, particularly GQDs-Cl and Cl-GQDs-OH, can effectively modulate TDP-43 phase separation and pathological aggregation.
• These findings suggest a novel therapeutic avenue for neurodegenerative diseases driven by proteinopathies.
• This study provides a foundation for designing advanced GQDs to control protein condensation and aggregation.