title: A novel snRNA-like transcript affects amyloidogenesis and cell cycle progression through perturbation of Fe65L1 (APBB2) alternative splicing.
abstract: FE65 proteins constitute a family of adaptors which modulates the processing of amyloid precursor protein and the consequent amyloid β production. Thus, they have been involved in the complex and partially unknown cascade of reactions at the base of Alzheimer's disease etiology. However, FE65 and FE65-like proteins may be linked to neurodegeneration through the regulation of cell cycle in post-mitotic neurons. In this work we disclose novel molecular mechanisms by which APBB2 can modulate APP processing. We show that APBB2 mRNA splicing, driven by the over-expression of a novel non-coding RNA named 45A, allow the generation of alternative protein forms endowed with differential effects on Aβ production, cell cycle control, and DNA damage response. 45A overexpression also favors cell transformation and tumorigenesis leading to a marked increase of malignancy of neuroblastoma cells. Therefore, our results highlight a novel regulatory pathway of considerable interest linking APP processing with cell cycle regulation and DNA-surveillance systems, that may represent a molecular mechanism to induce neurodegeneration in post-mitotic neurons.
authors.affiliation: Dept. of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Penna
authors.forename: Irene
authors.initials: I
authors.lastname: Vassallo
authors.forename: Mario
authors.initials: M
authors.lastname: Nizzari
authors.forename: Debora
authors.initials: D
authors.lastname: Russo
authors.forename: Delfina
authors.initials: D
authors.lastname: Costa
authors.forename: Paola
authors.initials: P
authors.lastname: Menichini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Claudio
authors.initials: C
authors.lastname: Russo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Dieci
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.forename: Aldo
authors.initials: A
authors.lastname: Pagano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015162:Micronucleus Tests; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D012342:RNA, Small Nuclear / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C466684:APBB2 protein, human; C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger; D012342:RNA, Small Nuclear