期刊
CELL REPORTS
卷 12, 期 2, 页码 335-345出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.06.019
关键词
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类别
资金
- Target-ALS
- ALS Association
- Project A.L.S.
- NIH/NINDS [NS072428-04, NS088009-02, NS078614-02, NS062055-03, NS042269-05A2, NS072182-01]
- NIH Roadmap National Centers for Biomedical Computing [5U54CA121852-08]
- US Department of Defense [W81XWH-12-1-0431, SRI 5-21306, W81XWH-13-1-0416]
- Columbia University
- NIEHS Center of Northern Manhattan [NIEHS ES009089]
- Philippe Foundation
Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, interactome''), whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS), characterized by a loss of spinal motor neurons (MNs). Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-kappa B, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-kappa B drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cellspecific mechanisms of neurodegeneration.
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