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The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo

(2012) JOURNAL OF BIOLOGICAL CHEMISTRY. 287(31). p.25927-25940
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Abstract
The beta-site amyloid precursor protein-cleaving enzyme BACE1 is a prime drug target for Alzheimer disease. However, the function and the physiological substrates of BACE1 remain largely unknown. In this work, we took a quantitative proteomic approach to analyze the secretome of primary neurons after acute BACE1 inhibition, and we identified several novel substrate candidates for BACE1. Many of these molecules are involved in neuronal network formation in the developing nervous system. We selected the adhesion molecules L1 and CHL1, which are crucial for axonal guidance and maintenance of neural circuits, for further validation as BACE1 substrates. Using both genetic BACE1 knock-out and acute pharmacological BACE1 inhibition in mice and cell cultures, we show that L1 and CHL1 are cleaved by BACE1 under physiological conditions. The BACE1 cleavage sites at the membrane-proximal regions of L1 (between Tyr(1086) and Glu(1087)) and CHL1 (between Gln(1061) and Asp(1062)) were determined by mass spectrometry. This work provides molecular insights into the function and the pathways in which BACE1 is involved, and it will help to predict or interpret possible side effects of BACE1 inhibitor drugs in current clinical trials.
Keywords
MICE DEFICIENT, GAMMA-SECRETASE, NEURITE OUTGROWTH, CLOSE HOMOLOG, SPINAL-CORD-INJURY, GATED SODIUM-CHANNELS, PERIPHERAL NERVOUS-SYSTEM, OLFACTORY SENSORY NEURONS, ALZHEIMERS BETA-SECRETASE, AMYLOID PRECURSOR PROTEIN

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Chicago
Zhou, LuJia, Soraia Barao, Mathias Laga, Katrijn Bockstael, Marianne Borgers, Harry Gijsen, Wim Annaert, et al. 2012. “The Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo.” Journal of Biological Chemistry 287 (31): 25927–25940.
APA
Zhou, L., Barao, S., Laga, M., Bockstael, K., Borgers, M., Gijsen, H., Annaert, W., et al. (2012). The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. JOURNAL OF BIOLOGICAL CHEMISTRY, 287(31), 25927–25940.
Vancouver
1.
Zhou L, Barao S, Laga M, Bockstael K, Borgers M, Gijsen H, et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. JOURNAL OF BIOLOGICAL CHEMISTRY. 2012;287(31):25927–40.
MLA
Zhou, LuJia, Soraia Barao, Mathias Laga, et al. “The Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo.” JOURNAL OF BIOLOGICAL CHEMISTRY 287.31 (2012): 25927–25940. Print.
@article{3048755,
  abstract     = {The beta-site amyloid precursor protein-cleaving enzyme BACE1 is a prime drug target for Alzheimer disease. However, the function and the physiological substrates of BACE1 remain largely unknown. In this work, we took a quantitative proteomic approach to analyze the secretome of primary neurons after acute BACE1 inhibition, and we identified several novel substrate candidates for BACE1. Many of these molecules are involved in neuronal network formation in the developing nervous system. We selected the adhesion molecules L1 and CHL1, which are crucial for axonal guidance and maintenance of neural circuits, for further validation as BACE1 substrates. Using both genetic BACE1 knock-out and acute pharmacological BACE1 inhibition in mice and cell cultures, we show that L1 and CHL1 are cleaved by BACE1 under physiological conditions. The BACE1 cleavage sites at the membrane-proximal regions of L1 (between Tyr(1086) and Glu(1087)) and CHL1 (between Gln(1061) and Asp(1062)) were determined by mass spectrometry. This work provides molecular insights into the function and the pathways in which BACE1 is involved, and it will help to predict or interpret possible side effects of BACE1 inhibitor drugs in current clinical trials.},
  author       = {Zhou, LuJia and Barao, Soraia and Laga, Mathias and Bockstael, Katrijn and Borgers, Marianne and Gijsen, Harry and Annaert, Wim and Moechars, Diederik and Mercken, Marc and Gevaert, Kris and De Strooper, Bart},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keyword      = {MICE DEFICIENT,GAMMA-SECRETASE,NEURITE OUTGROWTH,CLOSE HOMOLOG,SPINAL-CORD-INJURY,GATED SODIUM-CHANNELS,PERIPHERAL NERVOUS-SYSTEM,OLFACTORY SENSORY NEURONS,ALZHEIMERS BETA-SECRETASE,AMYLOID PRECURSOR PROTEIN},
  language     = {eng},
  number       = {31},
  pages        = {25927--25940},
  title        = {The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo},
  url          = {http://dx.doi.org/10.1074/jbc.M112.377465},
  volume       = {287},
  year         = {2012},
}

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