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Toxic PR n poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export

2017; National Academy of Sciences; Volume: 114; Issue: 7 Linguagem: Inglês

10.1073/pnas.1620293114

1091-6490

Kevin Shi, Eiichiro Mori, Zehra F. Nizami, Yi Lin, Masato Kato, Siheng Xiang, Leeju C. Wu, Ming Ding, Yonghao Yu, Joseph G. Gall, Steven L. McKnight,

Neurogenetic and Muscular Disorders Research

Significance A hexanucleotide repeat expansion in the first intron of the C9orf72 gene represents the most prominent form of heritable amyotrophic lateral sclerosis. Bidirectional transcription and ATG-independent translation of the expanded (GGGGCC) n repeat specifies the production of toxic glycine:arginine (GR n ) and proline:arginine (PR n ) poly-dipeptides. The present study provides evidence that the PR n poly-dipeptide binds directly to the central channel of nuclear pores, causing inhibition of both the import and export of macromolecules to and from the nucleus. Nuclear pore binding is shown to be mediated via direct interaction between the toxic PR n poly-dipeptide and polymeric forms of nuclear pore proteins enriched in phenylalanine:glycine repeats.