期刊
ACTA NEUROPATHOLOGICA
卷 135, 期 3, 页码 427-443出版社
SPRINGER
DOI: 10.1007/s00401-017-1796-5
关键词
ALS; C9orf72; DPR; RNA toxicity; Pur-alpha; p62; Zebrafish
资金
- European Research Council under the European's Seventh Framework Programme (FP7) under the Euro-MOTOR project [259867]
- ERC [340429]
- Research Foundation Flanders (FWO Flanders) [G.0983.14N]
- University of Leuven [GOA/11/014, C14/17/107]
- University of Leuven ['Opening the Future' fund]
- Interuniversity Attraction Poles program of the Belgian Federal Science Policy Office [P7/16]
- ALS Liga (Belgium)
- Association Belge contre les Maladies Neuro-Musculaires (ABMM)
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- 'Hart voor ALS' Fund, KU Leuven
- Agency for Innovation by Science and Technology (IWT) Flanders
- MRC [UKDRI-1006] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2016A-6, ARUK-PhD2012-29, ARUK-PPG2012A-14] Funding Source: researchfish
- Medical Research Council [UKDRI-6003, UKDRI-1006] Funding Source: researchfish
- Motor Neurone Disease Association [Isaacs/Apr13/818-791] Funding Source: researchfish
- European Research Council (ERC) [340429] Funding Source: European Research Council (ERC)
The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 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 of C9orf72-associated ALS/FTD.
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