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

Scientific Reports
Kohsuke KanekuraMasahiko Kuroda

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 pol...Continue Reading

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Citations

Aug 14, 2020·Bioconjugate Chemistry·John BowenBalaji M Rao
Apr 4, 2021·International Journal of Molecular Sciences·Wanil KimKyung-Ha Lee
May 1, 2021·Langmuir : the ACS Journal of Surfaces and Colloids·Chen ChenYuhei Hayamizu
May 11, 2021·Frontiers in Cellular Neuroscience·Daniel A SolomonSarah Mizielinska
Jul 31, 2020·Biophysical Journal·Hamidreza JafariniaPatrick R Onck
Sep 10, 2021·The Journal of Cell Biology·Chen ChenKohsuke Kanekura
Sep 8, 2021·Molecular Pharmaceutics·Yujing DuRongfu Wang
Dec 16, 2021·American Journal of Physiology. Cell Physiology·Kohsuke KanekuraMasahiko Kuroda

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Methods Mentioned

BETA
electrophoresis
fluorescence recovery after photobleaching
crosslinking assay
Fluorescence
circular dichroism
phage display
Assay
PCR
confocal microscopy

Software Mentioned

ImageJ

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