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Open Access 01-10-2014 | Original Paper

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

Authors: Yong-Jie Zhang, Karen Jansen-West, Ya-Fei Xu, Tania F. Gendron, Kevin F. Bieniek, Wen-Lang Lin, Hiroki Sasaguri, Thomas Caulfield, Jaime Hubbard, Lillian Daughrity, Jeannie Chew, Veronique V. Belzil, Mercedes Prudencio, Jeannette N. Stankowski, Monica Castanedes-Casey, Ena Whitelaw, Peter E. A. Ash, Michael DeTure, Rosa Rademakers, Kevin B. Boylan, Dennis W. Dickson, Leonard Petrucelli

Published in: Acta Neuropathologica | Issue 4/2014

Abstract

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.

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Title: Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress
Authors: Yong-Jie Zhang
Karen Jansen-West
Ya-Fei Xu
Tania F. Gendron
Kevin F. Bieniek
Wen-Lang Lin
Hiroki Sasaguri
Thomas Caulfield
Jaime Hubbard
Lillian Daughrity
Jeannie Chew
Veronique V. Belzil
Mercedes Prudencio
Jeannette N. Stankowski
Monica Castanedes-Casey
Ena Whitelaw
Peter E. A. Ash
Michael DeTure
Rosa Rademakers
Kevin B. Boylan
Dennis W. Dickson
Leonard Petrucelli
Publication date: 01-10-2014
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2014
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-014-1336-5

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Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

Abstract

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Abstract

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