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Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress
- Source :
- Acta Neuropathologica, Acta neuropathologica
- Publication Year :
- 2014
- Publisher :
- Springer Berlin Heidelberg, 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. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1336-5) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
Cholagogues and Choleretics
Proteasome activity
Protein Structure, Secondary
Salubrinal
chemistry.chemical_compound
Mice
0302 clinical medicine
Cells, Cultured
Aged, 80 and over
0303 health sciences
DNA Repeat Expansion
Brain
Translation (biology)
Middle Aged
Endoplasmic Reticulum Stress
3. Good health
Expanded repeat
Frontotemporal Dementia
Female
ER stress
Cell Nucleolus
Adult
Neurite
Clinical Neurology
C9ORF72
Nerve Tissue Proteins
Biology
Antibodies
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Animals
Humans
Poly(GA) proteins
030304 developmental biology
Aged
Original Paper
C9orf72 Protein
Endoplasmic reticulum
Amyotrophic Lateral Sclerosis
Proteins
Repeat-associated non-ATG translation
Embryo, Mammalian
Molecular biology
HEK293 Cells
chemistry
Gene Expression Regulation
Ran
Unfolded protein response
Neurology (clinical)
Human medicine
Trinucleotide repeat expansion
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 14320533 and 00016322
- Volume :
- 128
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica
- Accession number :
- edsair.doi.dedup.....3f54d842b19809e91ecba80239a0ad92