期刊
SCIENCE
卷 345, 期 6201, 页码 1192-1194出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1256800
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资金
- Alzheimer's Research UK
- Motor Neurone Disease Association
- Middlesex Hospital
- National Institute for Health Research (NIHR)/University College London Hospitals Biomedical Research Centre
- BRT
- NIHR Academic Clinical Fellowship
- UK Medical Research Council
- Wellcome Trust
- Max Planck Society
- Medical School General Charitable Trust
- MRC [G0701441, MR/J004022/1, MR/L021056/1, MR/K018523/1, G1000287] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PhD2012-29, ARUK-PPG2012A-14] Funding Source: researchfish
- Medical Research Council [MR/J004022/1, G0701441, MR/K018523/1, MR/L021056/1, G1000287] Funding Source: researchfish
- Motor Neurone Disease Association [Isaacs/Apr13/818-791] Funding Source: researchfish
- National Institute for Health Research [ACF-2012-18-009] Funding Source: researchfish
An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted RNA-only repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.
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