title: Increases of SET level and translocation are correlated with tau hyperphosphorylation at ser202/thr205 in CA1 of Ts65Dn mice.
abstract: SET is a multifunctional protein, but when present in the cytoplasm, acts as a powerful inhibitor of phosphatase 2A. We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, and SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205. The presence of SET in the cytoplasm in DS brains may play a role in the progression of the disease. Here, we show that in CA1 of 3-month-old Ts65Dn mice modeling DS, SET level is increased, and SET is translocated to the cytoplasm and associated with tau hyperphosphorylations at ser202/thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains. Tau hyperphosphorylation at ser356 and activation of other phosphatase 2A targets such as the mammalian target of rapamycin and adenosine monophosphate protein kinases were also observed, suggesting deleterious mechanisms. We propose Ts65Dn mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation to slow down disease progression.
authors.affiliation: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dorard
authors.affiliation: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Gorisse-Hussonnois
authors.affiliation: EA 4064, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guihenneuc-Jouyaux
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et la Moelle épinière, ICM, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Albac
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et la Moelle épinière, ICM, Paris, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Potier
authors.affiliation: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Electronic address: bernadette.allinquant@inserm.fr.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Allinquant
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000628:therapy*; D015870:Gene Expression; D056488:Histone Chaperones; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport; D012694:Serine; D020123:Sirolimus; D013912:Threonine; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D015513:Oncogene Proteins; C557500:SET protein, mouse; D016875:tau Proteins; D013912:Threonine; D012694:Serine; D054648:Protein Phosphatase 2; D020123:Sirolimus
keywords: Caspase cleaved APP; Hippocampus; SET translocation; Tau hyperphosphorylation; Ts65Dn mice