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

Hong Zhang, Huazhang Guo, Danni Li, Yiling Zhang, Shengnan Zhang, Wenyan Kang, Cong Liu, Weidong Le, Liang Wang (), Dan Li () and Bin Dai ()
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Hong Zhang: Shanghai Jiao Tong University
Huazhang Guo: Shanghai University
Danni Li: Shanghai Jiao Tong University
Yiling Zhang: Shanghai Jiao Tong University
Shengnan Zhang: Chinese Academy of Sciences
Wenyan Kang: Shanghai Jiao Tong University School of Medicine
Cong Liu: Chinese Academy of Sciences
Weidong Le: Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital
Liang Wang: Shanghai University
Dan Li: Shanghai Jiao Tong University
Bin Dai: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract TDP-43 is implicated in the dynamic formation of nuclear bodies and stress granules through phase separation. In diseased states, it can further condense into pathological aggregates in the nucleus and cytoplasm, contributing to the onset of amyotrophic lateral sclerosis. In this study, we evaluate the effect of graphene quantum dots (GQDs) with different functional groups on TDP-43’s phase separation and aggregation in various cellular locations. We find that halogen atom-doped GQDs (GQDs-Cl, Cl-GQDs-OH) penetrate the nuclear envelope, inhibiting the assembly of TDP-43 nuclear bodies and stress granules under oxidative stress or hyperosmotic environments, and reduce amyloid aggregates and disease-associated phosphorylation of TDP-43. Mechanistic analysis reveals GQDs-Cl and Cl-GQDs-OH modulate TDP-43 phase separation through hydrophobic and electrostatic interactions. Our findings highlight the potential of GQDs-Cl and Cl-GQDs-OH in modulating nuclear protein condensation and pathological aggregation, offering direction for the innovative design of GQDs to modulate protein phase separation and aggregation.

Date: 2024
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DOI: 10.1038/s41467-024-47167-x

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