title: Membrane tethering of APP c-terminal fragments is a prerequisite for T668 phosphorylation preventing nuclear sphere generation.
abstract: A central molecular hallmark of Alzheimer's disease (AD) is the β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP), which causes the generation of different c-terminal fragments like C99, AICD57, or AICD50 that fully or in part contain the APP transmembrane domain. In this study, we demonstrate that membrane-tethered C99 is phosphorylated by JNK3A at residue T668 (APP695 numbering) to a higher extent than AICD57, whereas AICD50 is not capable of being phosphorylated. The modification decreases the turnover of APP, while the blockade of APP cleavage increases APP phosphorylation. Generation of nuclear spheres, complexes consisting of the translocated AICD, FE65 and other proteins, is significantly reduced as soon as APP c-terminal fragments are accessible for phosphorylation. This APP modification, which we identified as significantly reduced in high plaque-load areas of the human brain, is linearly dependent on the level of APP expression. Accordingly, we show that APP abundance is likewise capable of modulating nuclear sphere generation. Thus, the precise and complex regulation of APP phosphorylation, abundance, and cleavage impacts the generation of nuclear spheres, which are under discussion of being of relevance in neurodegeneration and dementia. Future pharmacological manipulation of nuclear sphere generation may be a promising approach for AD treatment.
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bukhari
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kolbe
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Leonhardt
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Loosse
authors.affiliation: Molecular Biology II, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, Universitätsstraße 5, 45117 Essen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schröder
authors.affiliation: Molecular Biology II, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, Universitätsstraße 5, 45117 Essen, Germany.
authors.forename: Shirley
authors.initials: S
authors.lastname: Knauer
authors.affiliation: Functional Proteomics, Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.affiliation: Cell Signaling in Neurodegeneration (CSIN), Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany. Electronic address: thorsten.t.mueller@rub.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding
chemical_list: D016564:Amyloid beta-Protein Precursor; D010769:Phosphothreonine; D048057:Mitogen-Activated Protein Kinase 10; D053829:Amyloid Precursor Protein Secretases
keywords: APP cleavage; APP intracellular domain (AICD); APP phosphorylation; Alzheimer's disease; Amyloid precursor protein (APP); Nuclear spheres