Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides

Kohsuke Kanekura, Yuichiro Harada, Mao Fujimoto, Takuya Yagi, Yuhei Hayamizu, Kentaro Nagaoka, Masahiko Kuroda

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Abstract

Cell-penetrating peptides (CPPs) including arginine-rich peptides are attracting a lot of attention due to their potential as a novel intracellular drug delivery tool without substantial toxicity. On the other hand, disease-associated arginine-rich CPPs, such as poly-PR and poly-GR translated from C9orf72 gene, also efficiently enter neuronal cells and then kill them. Although both non-harmful CPPs and harmful poly-PR/GR penetrate the plasma membrane using same arginine residues, little is known about the factors which determine the toxicity of the pathogenic CPPs. Here, we show that poly-PR and poly-GR, but not other Arg-rich CPPs, specifically distributed to nucleolus via interaction with RNA. Importantly, C9orf72-dipeptides, but not other Arg-rich CPPs, caused inhibition of protein translation and cell death. Raising extracellular pH enhanced the cell penetration of poly-PR. The repeat number of (PR) affected the secondary structure and determined the intracellular delivery rate and neurotoxicity, and enforced intracellular delivery of non-penetrating short poly-PR peptide caused cell death, suggesting that modulation of extracellular environment to inhibit the uptake of Arg-rich dipeptides might be a drug target against poly-PR/GR-mediated neurotoxicity.

Original languageEnglish
Article number12740
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

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    Kanekura, K., Harada, Y., Fujimoto, M., Yagi, T., Hayamizu, Y., Nagaoka, K., & Kuroda, M. (2018). Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides. Scientific Reports, 8(1), [12740]. https://doi.org/10.1038/s41598-018-31096-z