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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

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Cell-Penetrating Peptides
Dipeptides
Arginine
Membranes
Cell Death
Peptides
Protein Biosynthesis
Pharmaceutical Preparations
Cell Membrane
RNA
Genes

ASJC Scopus subject areas

  • General

Cite this

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

Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides. / Kanekura, Kohsuke; Harada, Yuichiro; Fujimoto, Mao; Yagi, Takuya; Hayamizu, Yuhei; Nagaoka, Kentaro; Kuroda, Masahiko.

In: Scientific Reports, Vol. 8, No. 1, 12740, 01.12.2018.

Research output: Contribution to journalArticle

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, vol. 8, no. 1, 12740. https://doi.org/10.1038/s41598-018-31096-z
Kanekura, Kohsuke ; Harada, Yuichiro ; Fujimoto, Mao ; Yagi, Takuya ; Hayamizu, Yuhei ; Nagaoka, Kentaro ; Kuroda, Masahiko. / Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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