Document Type

Article

Publication Date

3-28-2024

Comments

This article is the author's final published version in Communications Biology, Volume 7, Issue 1, 2024, Article number 376.

The published version is available at https://doi.org/10.1038/s42003-024-06071-2.

Copyright © The Author(s) 2024

Abstract

Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.

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Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Supplementary Figures and Tables.pdf (5333 kB)
Supplementary Information
Description of Supplementary Materials.docx (15 kB)
Description of Supplementary Materials
Supplementary Movie 1.mp4 (187388 kB)
Supplementary Movie 1
Supplementary Movie 2.mp4 (28296 kB)
Supplementary Movie 2
Reporting Summary Commun Biol.pdf (1621 kB)
Reporting Summary

PubMed ID

38548902

Language

English

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