A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

AbstractThe exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion inC9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine –arginine and proline–arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis ofC9orf72-associated ALS/FTD.
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
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Source: Cell - Category: Cytology Source Type: research
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Source: PLOS Currents Huntington Disease - Category: Neurology Authors: Source Type: research
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Source: Cell - Category: Cytology Source Type: research
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Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
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Source: Acta Neuropathologica - Category: Neurology Source Type: research
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Source: eLife - Category: Biomedical Science Tags: Biochemistry and Chemical Biology Human Biology and Medicine Source Type: research
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Source: Nature Reviews Neurology - Category: Neurology Authors: Source Type: research
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Source: Toxicon - Category: Toxicology Authors: Tags: Toxicon Source Type: research
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