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DOI | 10.1038/s41467-018-06320-z |
C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity | |
Selvaraj, Bhuvaneish T.1,2,3; Livesey, Matthew R.2,3,4; Zhao, Chen1,2,3; Gregory, Jenna M.2,3; James, Owain T.2,3,4; Cleary, Elaine M.1,2,3; Chouhan, Amit K.2,5; Gane, Angus B.1,2,3; Perkins, Emma M.2,3,4; Dando, Owen4,6; Lillico, Simon G.7,8; Lee, Youn-Bok9; Nishimura, Agnes L.9; Poreci, Urjana10; Thankamony, Sai10; Pray, Meryll10; Vasistha, Navneet A.1,6; Magnani, Dario1,2,3; Borooah, Shyamanga1; Burr, Karen1,2,3; Story, David1,2,3; McCampbell, Alexander11; Shaw, Christopher E.9; Kind, Peter C.4,6; Aitman, Timothy J.12; Whitelaw, C. Bruce A.7,8; Wilmut, Ian1; Smith, Colin2,3; Miles, Gareth B.2,5; Hardingham, Giles E.2,4,13; Wyllie, David J. A.2,4,6; Chandran, Siddharthan1,2,3,6,13 | |
2018-01-24 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | Scotland; India; England; USA |
英文摘要 | Mutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-Seq and electrophysiological studies on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca2+-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs. We also demonstrate that MN-specific dysregulation of AMPAR expression is also present in C9ORF72 patient post-mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant C9ORF72 MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000423155700005 |
WOS关键词 | AMYOTROPHIC-LATERAL-SCLEROSIS ; MESSENGER-RNA EXPRESSION ; GLUTAMATE RECEPTORS ; MOLECULAR-CHANGE ; MOUSE MODEL ; DEATH ; ALS ; PROTEINS ; MATURATION ; BRAIN |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204004 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland; 2.Univ Edinburgh, Euan MacDonald Ctr MND Res, Edinburgh EH16 4SB, Midlothian, Scotland; 3.Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland; 4.Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland; 5.Univ St Andrews, Sch Psychol & Neurosci, St Andrews KY16 9JP, Fife, Scotland; 6.inStem, Ctr Brain Dev & Repair, Bangalore 560065, Karnataka, India; 7.Univ Edinburgh, Roslin Inst, Edinburgh EH25 9RG, Midlothian, Scotland; 8.Univ Edinburgh, RD SVS, Edinburgh EH25 9RG, Midlothian, Scotland; 9.Kings Coll London, Maurice Wohl Clin Neurosci Inst, London SE5 8AF, England; 10.Biogen, Global Biomarker & Drug Discovery, Cambridge, MA 02142 USA; 11.Biogen, Neurol Res, Cambridge, MA 02142 USA; 12.Univ Edinburgh, MRC Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland; 13.Univ Edinburgh, UK DRI Inst, Edinburgh EH16 4UU, Midlothian, Scotland |
推荐引用方式 GB/T 7714 | Selvaraj, Bhuvaneish T.,Livesey, Matthew R.,Zhao, Chen,et al. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Selvaraj, Bhuvaneish T..,Livesey, Matthew R..,Zhao, Chen.,Gregory, Jenna M..,James, Owain T..,...&Chandran, Siddharthan.(2018).C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity.NATURE COMMUNICATIONS,9. |
MLA | Selvaraj, Bhuvaneish T.,et al."C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity".NATURE COMMUNICATIONS 9(2018). |
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