title: FE65 and FE65L1 share common synaptic functions and genetically interact with the APP family in neuromuscular junction formation.
abstract: The FE65 adaptor proteins (FE65, FE65L1 and FE65L2) bind proteins that function in diverse cellular pathways and are essential for specific biological processes. Mice lacking both FE65 and FE65L1 exhibit ectopic neuronal positioning in the cortex and muscle weakness. p97FE65-KO mice, expressing a shorter FE65 isoform able to bind amyloid precursor protein family members (APP, APLP1, APLP2), develop defective long-term potentiation (LTP) and aged mice display spatial learning and memory deficits that are absent from young mice. Here, we examined the central and peripheral nervous systems of FE65-KO, FE65L1-KO and FE65/FE65L1-DKO mice. We find spatial learning and memory deficits in FE65-KO and FE65L1-KO mice. Severe motor impairments, anxiety, hippocampal LTP deficits and neuromuscular junction (NMJ) abnormalities, characterized by decreased size and reduced apposition of pre- and postsynaptic sites, are observed in FE65/FE65L1-DKO mice. As their NMJ deficits resemble those of mutant APP/APLP2-DKO mice lacking the FE65/FE65L1 binding site, the NMJs of APLP2/FE65-DKO and APLP2/FE65L1-DKO mice were analyzed. NMJ deficits are aggravated in these mice when compared to single FE65- and FE65L1-KO mice. Together, our data demonstrate a role for FE65 proteins at central and peripheral synapses possibly occurring downstream of cell surface-associated APP/APLPs.
authors.affiliation: Division of Human Biology and Human Genetics, Erwin-Schrödinger-Straße13, 67663 Kaiserslautern, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Strecker
authors.affiliation: Department of Cellular Neurobiology, Technical University of Braunschweig, Spielmannstraße 7, 38106 Braunschweig, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Ludewig
authors.affiliation: Division of Animal Physiology, University of Kaiserslautern, Erwin-Schrödinger-Straße 13, 67663 Kaiserslautern, Germany.|Institute of Physiological Chemistry, University of Marburg, Karl-von-Frisch-Straße 1, 35032 Marburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Rust
authors.affiliation: Centre for Molecular Biology (ZMBH) University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Tabea A
authors.initials: TA
authors.lastname: Mundinger
authors.affiliation: Division of Animal Physiology, University of Kaiserslautern, Erwin-Schrödinger-Straße 13, 67663 Kaiserslautern, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Görlich
authors.affiliation: Division of Animal Physiology, University of Kaiserslautern, Erwin-Schrödinger-Straße 13, 67663 Kaiserslautern, Germany.
authors.forename: Elisa G
authors.initials: EG
authors.lastname: Krächan
authors.affiliation: Division of Human Biology and Human Genetics, Erwin-Schrödinger-Straße13, 67663 Kaiserslautern, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Mehrfeld
authors.affiliation: Center for Translational Neurodegeneration Research, UT Southwestern, Dallas, TX, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Cellular Neurobiology, Technical University of Braunschweig, Spielmannstraße 7, 38106 Braunschweig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Suzanne Y
authors.initials: SY
authors.lastname: Guénette
authors.affiliation: Division of Human Biology and Human Genetics, Erwin-Schrödinger-Straße13, 67663 Kaiserslautern, Germany.|Centre for Molecular Biology (ZMBH) University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001007:Anxiety; D002352:Carrier Proteins / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D004843:Epistasis, Genetic; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007858:Learning; D017774:Long-Term Potentiation; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; C101886:Apbb2 protein, mouse; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins