期刊
EMBO MOLECULAR MEDICINE
卷 10, 期 1, 页码 22-31出版社
WILEY
DOI: 10.15252/emmm.201707850
关键词
amyotrophic lateral sclerosis; C9orf72; frontotemporal dementia; G-quadruplex
资金
- Thierry Latran Foundation
- ERC [H2020-ERC-2014-CoG-648716]
- MRC [MR/M008606/1]
- Brain Research Trust
- Alzheimer's Research UK [ARUK-PPG2012B-13]
- Leonard Wolfson Foundation
- NIH [GM111749]
- Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) - NCATS
- Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) - National Institute of Neurological Disorders and Stroke
- Wellcome Trust [107196/Z/14/Z]
- NIHR Queen Square Dementia Biomedical Research Unit
- Department of Health's NIHR Biomedical Research Centres funding scheme
- [101149/Z/13/A]
- Alzheimers Research UK [ARUK-PPG2012B-13, ARUK-PhD2012-29, ARUK-SRF2016B-2] Funding Source: researchfish
- Medical Research Council [UKDRI-1006, MR/M008606/1, UKDRI-1003] Funding Source: researchfish
- Motor Neurone Disease Association [Fratta/Jan15/946-795, Isaacs/Apr13/818-791] Funding Source: researchfish
- Muscular Dystrophy UK [16GRO-PS36-0055] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10082] Funding Source: researchfish
- Wellcome Trust [101149/Z/13/Z] Funding Source: researchfish
- Wellcome Trust [101149/Z/13/Z, 101149/Z/13/A] Funding Source: Wellcome Trust
- MRC [UKDRI-1003, MR/M008606/1, UKDRI-1006] Funding Source: UKRI
Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA. We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential.
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