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Neuroscience Bulletin

, Volume 35, Issue 5, pp 889–900 | Cite as

Poly-PR in C9ORF72-Related Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Causes Neurotoxicity by Clathrin-Dependent Endocytosis

  • Rui Wang
  • Xingyun Xu
  • Zongbing Hao
  • Shun Zhang
  • Dan Wu
  • Hongyang Sun
  • Chenchen Mu
  • Haigang Ren
  • Guanghui WangEmail author
Original Article

Abstract

GGGGCC repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9ORF72 produce five dipeptide repeat (DPR) proteins by an unconventional repeat-associated non-ATG (RAN) translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs (poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase (JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PR-induced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependent endocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.

Keywords

Amyotrophic lateral sclerosis C9ORF72 Poly-PR Clathrin ER stress 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81761148024 and 31871023), the National Key Scientific R&D Program of China (2016YFC1306000), Suzhou Clinical Research Center of Neurological Disease (Szzx201503), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, China.

Supplementary material

12264_2019_395_MOESM1_ESM.pdf (97 kb)
Supplementary material 1 (PDF 96 kb)

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Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Rui Wang
    • 1
  • Xingyun Xu
    • 1
  • Zongbing Hao
    • 1
  • Shun Zhang
    • 1
  • Dan Wu
    • 1
  • Hongyang Sun
    • 1
  • Chenchen Mu
    • 1
  • Haigang Ren
    • 1
  • Guanghui Wang
    • 1
    Email author
  1. 1.Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical SciencesSoochow UniversitySuzhouChina

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