Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress
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No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
Machine scores (provisional)
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- Teacher spread
- 0.254 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
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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The record
- Venue
- Acta Neuropathologica
- Topic
- Amyotrophic Lateral Sclerosis Research
- Field
- Medicine
- Canadian institutions
- —
- Funders
- Robert Packard Center for ALS Research, Johns Hopkins UniversityNational Institute of Neurological Disorders and StrokeNational Institute on AgingNational Institute of Environmental Health SciencesCanadian Institutes of Health ResearchNational Institutes of HealthJohns Hopkins UniversitySiragusa FoundationTarget ALSU.S. Department of Defense
- Keywords
- C9orf72Unfolded protein responseRanNeurotoxicityEndoplasmic reticulumTranslation (biology)BiologyNeuriteNeurodegenerationTrinucleotide repeat expansionProteasomeAmyotrophic lateral sclerosisFrontotemporal dementiaCell biologyStress granuleGeneticsChemistryGeneDementiaMessenger RNAMedicineDiseaseToxicityPathology
- Has abstract in OpenAlex
- yes