【摘 要】
：
GGGGCC repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FrD).It has been reported that hexanucleotide repeat expansions in C9ORF72 produce five dipeptide repeat (DPR) prote
【机 构】
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Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Depa
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GGGGCC repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FrD).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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