title: FE65 regulates and interacts with the Bloom syndrome protein in dynamic nuclear spheres - potential relevance to Alzheimer's disease.
abstract: The intracellular domain of the amyloid precursor protein (AICD) is generated following cleavage of the precursor by the γ-secretase complex and is involved in membrane to nucleus signaling, for which the binding of AICD to the adapter protein FE65 is essential. Here we show that FE65 knockdown causes a downregulation of the protein Bloom syndrome protein (BLM) and the minichromosome maintenance (MCM) protein family and that elevated nuclear levels of FE65 result in stabilization of the BLM protein in nuclear mobile spheres. These spheres are able to grow and fuse, and potentially correspond to the nuclear domain 10. BLM plays a role in DNA replication and repair mechanisms and FE65 was also shown to play a role in DNA damage response in the cell. A set of proliferation assays in our work revealed that FE65 knockdown in HEK293T cells reduced cell replication. On the basis of these results, we hypothesize that nuclear FE65 levels (nuclear FE65/BLM containing spheres) may regulate cell cycle re-entry in neurons as a result of increased interaction of FE65 with BLM and/or an increase in MCM protein levels. Thus, FE65 interactions with BLM and MCM proteins may contribute to the neuronal cell cycle re-entry observed in brains affected by Alzheimer's disease.
authors.affiliation: Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, 44801 Bochum, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schrötter
authors.forename: Thomas
authors.initials: T
authors.lastname: Mastalski
authors.forename: Fabian M
authors.initials: FM
authors.lastname: Nensa
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
authors.forename: Christina
authors.initials: C
authors.lastname: Loosse
authors.forename: Kathy
authors.initials: K
authors.lastname: Pfeiffer
authors.forename: Fouzi El
authors.initials: FE
authors.lastname: Magraoui
authors.forename: Harald W
authors.initials: HW
authors.lastname: Platta
authors.forename: Ralf
authors.initials: R
authors.lastname: Erdmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Theiss
authors.forename: Julian
authors.initials: J
authors.lastname: Uszkoreit
authors.forename: Martin
authors.initials: M
authors.lastname: Eisenacher
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*
chemical_list: C091042:APBB1 protein, human; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: Mass spectrometry; Morbus Alzheimer; Neurodegeneration; Nuclear translocation; Signal transduction; Stable FE65 knockdown model