title: Antagonistic Effects of BACE1 and APH1B-γ-Secretase Control Axonal Guidance by Regulating Growth Cone Collapse.
abstract: ΒACE1 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-γ-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 γ-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.
authors: VIB Center for the Biology of Disease, VIB-Leuven 3000, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Leuven 3000, Belgium.
authors: Soraia
authors: S
authors: Barão
authors: VIB Center for the Biology of Disease, VIB-Leuven 3000, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Leuven 3000, Belgium.
authors: Annette
authors: A
authors: Gärtner
authors: Instituto de Neurociencias, Universidad Miguel Hernandez-Consejo Superior de Investigaciones Científicas (UMH-CSIC), 03550 San Joan d'Alacant, Spain.
authors: Eduardo
authors: E
authors: Leyva-Díaz
authors: Department of Biochemistry and Biophysics, University of North Carolina (UNC), Chapel Hill, NC 27599, USA.
authors: Galina
authors: G
authors: Demyanenko
authors: VIB Center for the Biology of Disease, VIB-Leuven 3000, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Leuven 3000, Belgium.
authors: Sebastian
authors: S
authors: Munck
authors: VIB Center for the Biology of Disease, VIB-Leuven 3000, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Leuven 3000, Belgium.
authors: Tine
authors: T
authors: Vanhoutvin
authors: VIB Center for the Biology of Disease, VIB-Leuven 3000, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Leuven 3000, Belgium.
authors: Lujia
authors: L
authors: Zhou
authors: W.M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854-8082, USA; Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong 515041, China.
authors: Melitta
authors: M
authors: Schachner
authors: Instituto de Neurociencias, Universidad Miguel Hernandez-Consejo Superior de Investigaciones Científicas (UMH-CSIC), 03550 San Joan d'Alacant, Spain.
authors: Guillermina
authors: G
authors: López-Bendito
authors: Department of Biochemistry and Biophysics, University of North Carolina (UNC), Chapel Hill, NC 27599, USA.
authors: Patricia F
authors: PF
authors: Maness
authors: VIB Center for the Biology of Disease, VIB-Leuven 3000, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, Leuven 3000, Belgium; Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK. Electronic address: bart.destrooper@cme.vib-kuleuven.be.
authors: Bart
authors: B
authors: De Strooper
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D059748:Proteolysis; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C498195:Aph1b protein, mouse