NLS-Binding Deficient Kapβ2 Reduces Neurotoxicity via Selective Interaction With C9orf72-ALS/FTD Dipeptide Repeats

Authors

Kevin Kim, Thomas Jefferson UniversityFollow
Amandeep Girdhar, Thomas Jefferson UniversityFollow
Maria Elena Cicardi, Thomas Jefferson UniversityFollow
V. Kankate, Thomas Jefferson UniversityFollow
Miyuki Hayashi, Thomas Jefferson UniversityFollow
Ruoyu Yang, Thomas Jefferson UniversityFollow
Jenny Carey, Thomas Jefferson UniversityFollow
Charlotte M Fare
James Shorter
Gino Cingolani, Thomas Jefferson UniversityFollow
Davide Trotti, Thomas Jefferson UniversityFollow
Lin Guo, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

1-2-2025

Comments

This article is the author's final published version in Communications Biology, Volume 8, Issue 1, 2025, Article number 2.

The published version is available at https://doi.org/10.1038/s42003-024-07412-x.

Copyright © The Author(s) 2025

Abstract

Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity. Here, we use FUS as a model RBP to investigate the mechanism of R-DPR-induced aberrant RBP phase transition. We find that this phase transition can be mitigated by Kapβ2. However, as a nuclear import receptor and phase modifier for PY-NLS-containing RBPs, the function of WT Kapβ2 could lead to undesired interaction with its native substrates when used as therapeutics for C9-ALS/FTD. To address this issue, it is crucial to devise effective strategies that allow Kapβ2 to selectively target its binding to the R-DPRs, instead of the RBPs. We show that NLS-binding deficient Kapβ2_W460A:W730A can indeed selectively interact with R-DPRs in FUS assembly without affecting normal FUS phase separation. Importantly, Kapβ2_W460A:W730A prevents enrichment of poly(GR) in stress granules and mitigates R-DPR neurotoxicity. Thus, NLS-binding deficient Kapβ2 may be implemented as a potential therapeutic for C9-ALS/FTD.

Recommended Citation

Kim, Kevin; Girdhar, Amandeep; Cicardi, Maria Elena; Kankate, V.; Hayashi, Miyuki; Yang, Ruoyu; Carey, Jenny; Fare, Charlotte M; Shorter, James; Cingolani, Gino; Trotti, Davide; and Guo, Lin, "NLS-Binding Deficient Kapβ2 Reduces Neurotoxicity via Selective Interaction With C9orf72-ALS/FTD Dipeptide Repeats" (2025). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 274.
https://jdc.jefferson.edu/bmpfp/274

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

39747573