期刊
NEURON
卷 81, 期 5, 页码 1001-1008出版社
CELL PRESS
DOI: 10.1016/j.neuron.2014.01.011
关键词
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资金
- NIH [5 U42 RR006042]
- NIH/NINDS [NS062180, NS064191-01A1, NS042269-05A2, NS072182-01, NS062055-01A1, NS078614-01A1]
- U.S. Department of Defense [W81XWH-08-1-0522, W81XWH-12-1-0431]
- NIEHS [ES009089]
- Project A.L.S.
- P2ALS
- Target ALS
- ALS Association
- Muscular Dystrophy Association/Wings-over-Wall Street
- Parkinson's Disease Foundation
- Midwinter Night's Dream
- NIEHS Center of Northern Manhattan
- Philippe Foundation
- NIH/NCATS [TR000082-07]
- ALS COSMOS project [R01ES160348]
- Grants-in-Aid for Scientific Research [25461303] Funding Source: KAKEN
Most cases of neurodegenerative diseases are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS), we therefore devised a fully humanized coculture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem-cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this non-cell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptor-interacting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a potential therapeutic target for this incurable disease.
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