期刊
CELL REPORTS
卷 12, 期 9, 页码 1367-1376出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.07.059
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资金
- European Research Council (ERC) [ERC-2009-StG_20081210, ERC-2010-AG_268675]
- Fonds voor Wetenschappelijk Onderzoek (FWO)
- KU Leuven
- VIB, a Methusalem grant of the KU Leuven/Flemish Government
- Fundacao para a Ciencia e a Tecnologia (FCT) [POPH/FSE/FCT/SFRH/BD/71949/2010]
- Bax-Vanluffelen Chair for Alzheimer's Disease and Opening the Future of the Leuven Universiteit Fonds (LUF)
- CLME grant
- Inframouse
BACE1 is the major drug target for Alzheimer's disease, but we know surprisingly little about its normal function in the CNS. Here, we show that this protease is critically involved in semaphorin 3A (Sema3A)-mediated axonal guidance processes in thalamic and hippocampal neurons. An active membrane-bound proteolytic CHL1 fragment is generated by BACE1 upon Sema3A binding. This fragment relays the Sema3A signal via ezrin-radixin-moesin (ERM) proteins to the neuronal cytoskeleton. APH1B-gamma-secretase-mediated degradation of this fragment stops the Sema3A-induced collapse and sensitizes the growth cone for the next axonal guidance cue. Thus, we reveal a cycle of proteolytic activity underlying growth cone collapse and restoration used by axons to find their correct trajectory in the brain. Our data also suggest that BACE1 and g-secretase inhibition have physiologically opposite effects in this process, supporting the idea that combination therapy might attenuate some of the side effects associated with these drugs.
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