Unknown

Dataset Information

0

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


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.

SUBMITTER: Wang R 

PROVIDER: S-EPMC6754483 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Wang Rui R   Xu Xingyun X   Hao Zongbing Z   Zhang Shun S   Wu Dan D   Sun Hongyang H   Mu Chenchen C   Ren Haigang H   Wang Guanghui G  

Neuroscience bulletin 20190530 5


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  ...[more]

Similar Datasets

| S-EPMC8678157 | biostudies-literature
2019-02-04 | GSE112931 | GEO
| S-EPMC6985338 | biostudies-literature
| S-EPMC7492664 | biostudies-literature
| S-EPMC6520050 | biostudies-literature
| S-EPMC3527825 | biostudies-other
| S-EPMC7912327 | biostudies-literature
| S-EPMC6416930 | biostudies-literature
2013-11-12 | E-GEOD-51741 | biostudies-arrayexpress
2013-11-12 | GSE51741 | GEO