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The Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo

Zhou, Lujia, Barão, Soraia, Laga, Mathias, Bockstael, Katrijn, Borgers, Marianne, Gijsen, Harry, Annaert, Wim, Moechars, Diederik, Mercken, Marc, Gevaer, Kris, De Strooper, Bart·2012·Journal of Biological Chemistry
DOI 10.1074/jbc.m112.377465
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Abstract

The β-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.

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  • More than 40 substrate candidates for BACE1 were identified in recent proteomic studies in murine neurons or CSF, but only a few have been validated with functional or in vitro assays, including L1, CHL1, ENPP5 and PTPRN2.

    “More than 40 substrate candidates for BACE1 were identified in recent proteomic studies in murine neurons or cerebrospinal fluid (CSF), but only a few of them have been validated to date with functional or in vitro assays, including L1, CHL1, ENPP5 and PTPRN2 [12, 14–16].”

    From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [16]

  • Recent proteomic studies have identified more than 40 membrane proteins as potential BACE1 substrates.

    “Recent proteomic studies have identified more than 40 membrane proteins as potential BACE1 substrates [14–16].”

    From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [16]

  • L1CAM and CHL1 are BACE1 substrates involved in axon guidance.

    “L1 cell adhesion molecule (L1CAM) and neural cell adhesion molecule L1‐like protein (CHL1) are BACE1 substrates involved in axon guidance.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [31]

  • BACE-1 cleaves numerous substrates, conferring a wide spectrum of physiological and pathological activities.

    “BACE-1 cleaves numerous substrates, which confers this enzyme a wide spectrum of physiological and pathological activities (Kuhn et al., 2012; Zhou et al., 2012; Vassar et al., 2014), but it is indisputably its ability to process APP that has attracted much attention, especially in relation to AD.”

    From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Zhou et al., 2012

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Research works printed but not linked: 78

  1. Sinha, 1999, Purification and cloning of amyloid precursor protein β-secretase from human brain, Nature., 402, 537, 10.1038/990114 · DOI · Paper page
  2. Hussain, 1999, Identification of a novel aspartic protease (Asp-2) as β-secretase, Mol. Cell. Neurosci., 14, 419, 10.1006/mcne.1999.0811 · DOI · Paper page
  3. Yan, 1999, Membrane-anchored aspartyl protease with Alzheimer disease β-secretase activity, Nature., 402, 533, 10.1038/990107 · DOI · Paper page
  4. Lin, 2000, Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein, Proc. Natl. Acad. Sci. U.S.A., 97, 1456, 10.1073/pnas.97.4.1456 · DOI
  5. De Strooper, 2010, The secretases. Enzymes with therapeutic potential in Alzheimer disease, Nat. Rev. Neurol., 6, 99, 10.1038/nrneurol.2009.218 · DOI · Paper page
  6. Singer, 2005, Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model, Nat. Neurosci., 8, 1343, 10.1038/nn1531 · DOI
  7. Luo, 2001, Mice deficient in BACE1, the Alzheimer β-secretase, have normal phenotype and abolished β-amyloid generation, Nat. Neurosci., 4, 231, 10.1038/85059 · DOI · Paper page
  8. Laird, 2005, BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions, J. Neurosci., 25, 11693, 10.1523/JNEUROSCI.2766-05.2005 · DOI · Paper page
  9. Kobayashi, 2008, BACE1 gene deletion. Impact on behavioral function in a model of Alzheimer disease, Neurobiol. Aging., 29, 861, 10.1016/j.neurobiolaging.2007.01.002 · DOI · Paper page
  10. Ohno, 2006, Temporal memory deficits in Alzheimer mouse models. Rescue by genetic deletion of BACE1, Eur. J. Neurosci., 23, 251, 10.1111/j.1460-9568.2005.04551.x · DOI · Paper page
  11. Ohno, 2004, BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer disease, Neuron., 41, 27, 10.1016/S0896-6273(03)00810-9 · DOI · Paper page
  12. Wang, 2008, BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus, J. Neurosci., 28, 8677, 10.1523/JNEUROSCI.2440-08.2008 · DOI
  13. Harrison, 2003, BACE1 (β-secretase) transgenic and knock-out mice. Identification of neurochemical deficits and behavioral changes, Mol. Cell. Neurosci., 24, 646, 10.1016/S1044-7431(03)00227-6 · DOI · Paper page
  14. Dominguez, 2005, Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice, J. Biol. Chem., 280, 30797, 10.1074/jbc.M505249200 · DOI
  15. Hu, 2006, Bace1 modulates myelination in the central and peripheral nervous system, Nat. Neurosci., 9, 1520, 10.1038/nn1797 · DOI · Paper page
  16. Hitt, 2010, BACE1−/− mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization, Mol. Neurodegener., 5, 31, 10.1186/1750-1326-5-31 · DOI · Paper page
  17. Wong, 2005, β-Subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase, J. Biol. Chem., 280, 23009, 10.1074/jbc.M414648200 · DOI
  18. Kim, 2007, BACE1 regulates voltage-gated sodium channels and neuronal activity, Nat. Cell Biol., 9, 755, 10.1038/ncb1602 · DOI
  19. Kitazume, 2001, Alzheimer β-secretase, β-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase, Proc. Natl. Acad. Sci. U.S.A., 98, 13554, 10.1073/pnas.241509198 · DOI · Paper page
  20. Lichtenthaler, 2003, The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1, J. Biol. Chem., 278, 48713, 10.1074/jbc.M303861200 · DOI · Paper page
  21. Kuhn, 2007, Regulated intramembrane proteolysis of the interleukin-1 receptor II by α-, β-, and γ-secretase, J. Biol. Chem., 282, 11982, 10.1074/jbc.M700356200 · DOI · Paper page
  22. Li, 2004, Cleavage of amyloid-β precursor protein and amyloid-β precursor-like protein by BACE 1, J. Biol. Chem., 279, 10542, 10.1074/jbc.M310001200 · DOI · Paper page
  23. Pastorino, 2004, BACE (β-secretase) modulates the processing of APLP2 in vivo, Mol. Cell. Neurosci., 25, 642, 10.1016/j.mcn.2003.12.013 · DOI
  24. Hemming, 2009, Identification of β-secretase (BACE1) substrates using quantitative proteomics, PLoS One., 4, e8477, 10.1371/journal.pone.0008477 · DOI
  25. Maness, 2007, Neural recognition molecules of the immunoglobulin superfamily. Signaling transducers of axon guidance and neuronal migration, Nat. Neurosci., 10, 19, 10.1038/nn1827 · DOI
  26. Irintchev, A., Schachner, M. (2011) The injured and regenerating nervous system. Immunoglobulin superfamily members as key players. Neuroscientist 1.73858411419047 · DOI
  27. Montag-Sallaz, 2002, Misguided axonal projections, neural cell adhesion molecule 180 mRNA up-regulation, and altered behavior in mice deficient for the close homolog of L1, Mol. Cell. Biol., 22, 7967, 10.1128/MCB.22.22.7967-7981.2002 · DOI
  28. Pratte, 2003, Mice deficient for the close homolog of the neural adhesion cell L1 (CHL1) display alterations in emotional reactivity and motor coordination, Behav. Brain Res., 147, 31, 10.1016/S0166-4328(03)00114-1 · DOI
  29. Kenwrick, 2000, Neural cell recognition molecule L1. Relating biological complexity to human disease mutations, Hum. Mol. Genet., 9, 879, 10.1093/hmg/9.6.879 · DOI
  30. Frints, 2003, CALL interrupted in a patient with nonspecific mental retardation. Gene dosage-dependent alteration of murine brain development and behavior, Hum. Mol. Genet., 12, 1463, 10.1093/hmg/ddg165 · DOI
  31. Kurumaji, 2001, An association study between polymorphism of L1CAM gene and schizophrenia in a Japanese sample, Am. J. Med. Genet., 105, 99, 10.1002/1096-8628(20010108)105:1<99::AID-AJMG1071>3.0.CO;2-U · DOI
  32. Sakurai, 2002, An association between a missense polymorphism in the close homolog of L1 (CHL1, CALL) gene and schizophrenia, Mol. Psychiatry., 7, 412, 10.1038/sj.mp.4000973 · DOI
  33. Annaert, 1999, Presenilin 1 controls γ-secretase processing of amyloid precursor protein in pre-Golgi compartments of hippocampal neurons, J. Cell Biol., 147, 277, 10.1083/jcb.147.2.277 · DOI
  34. Ghesquiere, B., Jonckheere, V., Colaert, N., Van Durme, J., Timmerman, E., Goethals, M., Schymkowitz, J., Rousseau, F., Vandekerckhove, J., Gevaert, K. (2011) Redox proteomics of protein-bound methionine oxidation. Mol. Cell. Proteomics M110.006866-1-12 · DOI
  35. Colaert, 2010, Rover. A tool to visualize and validate quantitative proteomics data from different sources, Proteomics., 10, 1226, 10.1002/pmic.200900379 · DOI
  36. Helsens, 2010, ms_lims, a simple yet powerful open source laboratory information management system for MS-driven proteomics, Proteomics., 10, 1261, 10.1002/pmic.200900409 · DOI
  37. Beer, 1999, Metalloproteinase-mediated release of the ectodomain of L1 adhesion molecule, J. Cell Sci., 112, 2667, 10.1242/jcs.112.16.2667 · DOI
  38. Maretzky, 2005, L1 is sequentially processed by two differently activated metalloproteases and presenilin/γ-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth, Mol. Cell. Biol., 25, 9040, 10.1128/MCB.25.20.9040-9053.2005 · DOI
  39. Esterházy, 2011, Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass, Cell Metab., 14, 365, 10.1016/j.cmet.2011.06.018 · DOI · Paper page
  40. Lopes, 1999, Cross-talk between A1 and A2A adenosine receptors in the hippocampus and cortex of young adult and old rats, J. Neurophysiol., 82, 3196, 10.1152/jn.1999.82.6.3196 · DOI
  41. Nagy, 1984, Rapid preparation of synaptosomes from mammalian brain using nontoxic isoosmotic gradient material (Percoll), J. Neurochem., 43, 1114, 10.1111/j.1471-4159.1984.tb12851.x · DOI
  42. Huttner, 1983, Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation, J. Cell Biol., 96, 1374, 10.1083/jcb.96.5.1374 · DOI
  43. Zhou, 2011, Inhibition of β-secretase in vivo via antibody binding to unique loops (D and F) of BACE1, J. Biol. Chem., 286, 8677, 10.1074/jbc.M110.194860 · DOI
  44. Stachel, 2004, Structure-based design of potent and selective cell-permeable inhibitors of human β-secretase (BACE-1), J. Med. Chem., 47, 6447, 10.1021/jm049379g · DOI · Paper page
  45. Zhou, 2011, Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β′-site increases Aβ generation, EMBO Mol. Med., 3, 291, 10.1002/emmm.201100138 · DOI
  46. Leighton, 2001, Defining brain wiring patterns and mechanisms through gene trapping in mice, Nature., 410, 174, 10.1038/35065539 · DOI
  47. Miller, 2007, Expression of Plxdc2/TEM7R in the developing nervous system of the mouse, Gene Expr. Patterns., 7, 635, 10.1016/j.modgep.2006.12.002 · DOI
  48. Steegmaier, 1995, The E-selectin-ligand ESL-1 is a variant of a receptor for fibroblast growth factor, Nature., 373, 615, 10.1038/373615a0 · DOI
  49. Leshchyns'ka, 2006, The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles, Neuron., 52, 1011, 10.1016/j.neuron.2006.10.020 · DOI
  50. Persohn, 1990, Immunohistological localization of the neural adhesion molecules L1 and N-CAM in the developing hippocampus of the mouse, J. Neurocytol., 19, 807, 10.1007/BF01186812 · DOI
  51. Cao, 2012, The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease, Sci. Rep., 2, 231, 10.1038/srep00231 · DOI
  52. Zhao, 2007, β-Site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques. Implications for Alzheimer disease pathogenesis, J. Neurosci., 27, 3639, 10.1523/JNEUROSCI.4396-06.2007 · DOI · Paper page
  53. Vassar, 2009, The β-secretase enzyme BACE in health and Alzheimer disease. Regulation, cell biology, function, and therapeutic potential, J. Neurosci., 29, 12787, 10.1523/JNEUROSCI.3657-09.2009 · DOI · Paper page
  54. Turner, 2001, Subsite specificity of memapsin 2 (β-secretase). Implications for inhibitor design, Biochemistry., 40, 10001, 10.1021/bi015546s · DOI
  55. Hillenbrand, 1999, The close homolog of the neural adhesion molecule L1 (CHL1). Patterns of expression and promotion of neurite outgrowth by heterophilic interactions, Eur. J. Neurosci., 11, 813, 10.1046/j.1460-9568.1999.00496.x · DOI
  56. Honda, 2000, The coxsackievirus-adenovirus receptor protein as a cell adhesion molecule in the developing mouse brain, Brain Res. Mol. Brain Res., 77, 19, 10.1016/S0169-328X(00)00036-X · DOI
  57. Mandai, 2009, LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development, Neuron., 63, 614, 10.1016/j.neuron.2009.07.031 · DOI
  58. Falls, 2003, Neuregulins. Functions, forms, and signaling strategies, Exp. Cell Res., 284, 14, 10.1016/S0014-4827(02)00102-7 · DOI
  59. Selvais, 2011, Cell cholesterol modulates metalloproteinase-dependent shedding of low density lipoprotein receptor-related protein-1 (LRP-1) and clearance function, FASEB J., 25, 2770, 10.1096/fj.10-169508 · DOI
  60. Karagogeos, 2003, Neural GPI-anchored cell adhesion molecules, Front. Biosci., 8, s1304, 10.2741/1214 · DOI
  61. Suetterlin, 2012, Axonal ephrinA/EphA interactions, and the emergence of order in topographic projections, Semin. Cell Dev. Biol., 23, 1, 10.1016/j.semcdb.2011.10.015 · DOI
  62. Rajapaksha, 2011, The Alzheimer β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb, Mol. Neurodegener., 6, 88, 10.1186/1750-1326-6-88 · DOI
  63. Yamanaka, 2011, Increase of close homolog of cell adhesion molecule L1 in primary afferent by nerve injury and the contribution to neuropathic pain, J. Comp. Neurol., 519, 1597, 10.1002/cne.22588 · DOI
  64. Naus, 2004, Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death, J. Biol. Chem., 279, 16083, 10.1074/jbc.M400560200 · DOI
  65. Schlomann, 2000, Tumor necrosis factor α induces a metalloprotease-disintegrin, ADAM8 (CD 156). Implications for neuron-glia interactions during neurodegeneration, J. Neurosci., 20, 7964, 10.1523/JNEUROSCI.20-21-07964.2000 · DOI
  66. Dahme, 1997, Disruption of the mouse L1 gene leads to malformations of the nervous system, Nat. Genet., 17, 346, 10.1038/ng1197-346 · DOI
  67. Cohen, 1998, Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1, Curr. Biol., 8, 26, 10.1016/S0960-9822(98)70017-X · DOI
  68. Demyanenko, 1999, Abnormalities in neuronal process extension, hippocampal development, and the ventricular system of L1 knockout mice, J. Neurosci., 19, 4907, 10.1523/JNEUROSCI.19-12-04907.1999 · DOI
  69. Demyanenko, 2003, The L1 cell adhesion molecule is essential for topographic mapping of retinal axons, J. Neurosci., 23, 530, 10.1523/JNEUROSCI.23-02-00530.2003 · DOI
  70. Buhusi, 2008, L1 interaction with ankyrin regulates mediolateral topography in the retinocollicular projection, J. Neurosci., 28, 177, 10.1523/JNEUROSCI.3573-07.2008 · DOI
  71. Wright, 2007, Close homolog of L1 and neuropilin 1 mediates guidance of thalamocortical axons at the ventral telencephalon, J. Neurosci., 27, 13667, 10.1523/JNEUROSCI.2888-07.2007 · DOI
  72. Demyanenko, 2011, L1 and CHL1 cooperate in thalamocortical axon targeting, Cereb. Cortex., 21, 401, 10.1093/cercor/bhq115 · DOI
  73. Demyanenko, 2004, Close homolog of L1 modulates area-specific neuronal positioning and dendrite orientation in the cerebral cortex, Neuron., 44, 423, 10.1016/j.neuron.2004.10.016 · DOI
  74. Zhang, 2005, Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo, Proc. Natl. Acad. Sci. U.S.A., 102, 14883, 10.1073/pnas.0505164102 · DOI
  75. Roonprapunt, 2003, Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury, J. Neurotrauma., 20, 871, 10.1089/089771503322385809 · DOI
  76. Xu, 2004, Optic nerve regeneration in polyglycolic acid-chitosan conduits coated with recombinant L1-Fc, Neuroreport., 15, 2167, 10.1097/00001756-200410050-00004 · DOI
  77. Jakovcevski, 2007, Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury, J. Neurosci., 27, 7222, 10.1523/JNEUROSCI.0739-07.2007 · DOI
  78. Farah, 2011, Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system, J. Neurosci., 31, 5744, 10.1523/JNEUROSCI.6810-10.2011 · DOI

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Metadata

Authors
Zhou, L., Barão, S., Laga, M., Bockstael, K., Borgers, M., Gijsen, H., Annaert, W., Moechars, D., Mercken, M., Gevaer, K., & De Strooper, B.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2012-07
Volume
287
Issue
31
Pages
25927-25940
ISSN
0021-9258
DOI
10.1074/jbc.m112.377465
Cited by
167
References
8
Language
en
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