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

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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.

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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.

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  1. Rui Wang, Xingyun Xu and Zongbing Hao have contributed equally to this work.

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  1. Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Rui Wang, Xingyun Xu, Zongbing Hao, Shun Zhang, Dan Wu, Hongyang Sun, Chenchen Mu, Haigang Ren & Guanghui Wang

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Wang, R., Xu, X., Hao, Z. et al. Poly-PR in C9ORF72-Related Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Causes Neurotoxicity by Clathrin-Dependent Endocytosis. Neurosci. Bull. 35, 889–900 (2019). https://doi.org/10.1007/s12264-019-00395-4

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