title: Pathogenic PS1 phosphorylation at Ser367.
abstract: The high levels of serine (S) and threonine (T) residues within the Presenilin 1 (PS1) N-terminus and in the large hydrophilic loop region suggest that the enzymatic function of PS1/γ-secretase can be modulated by its 'phosphorylated' and 'dephosphorylated' states. However, the functional outcome of PS1 phosphorylation and its significance for Alzheimer's disease (AD) pathogenesis is poorly understood. Here, comprehensive analysis using FRET-based imaging reveals that activity-driven and Protein Kinase A-mediated PS1 phosphorylation at three domains (domain 1: T74, domain 2: S310 and S313, domain 3: S365, S366, and S367), with S367 being critical, is responsible for the PS1 pathogenic 'closed' conformation, and resulting increase in the Aβ42/40 ratio. Moreover, we have established novel imaging assays for monitoring PS1 conformation in vivo, and report that PS1 phosphorylation induces the pathogenic conformational shift in the living mouse brain. These phosphorylation sites represent potential new targets for AD treatment.
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Masato
authors.identifier: 0000-0002-1970-2462
authors.initials: M
authors.lastname: Maesako
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.|Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Horlacher
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Katarzyna M
authors.identifier: 0000-0001-5853-3465
authors.initials: KM
authors.lastname: Zoltowska
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Ksenia V
authors.initials: KV
authors.lastname: Kastanenka
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Svirsky
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Keller
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Li
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.affiliation: Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors.forename: Oksana
authors.identifier: 0000-0003-4898-5788
authors.initials: O
authors.lastname: Berezovska
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D031541:Fluorescence Resonance Energy Transfer; D051379:Mice; D061848:Optical Imaging; D010766:Phosphorylation; D053764:Presenilin-1 / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational
chemical_list: D053764:Presenilin-1
keywords: Alzheimer's disease; Förster resonance energy transfer; Presenilin 1; biochemistry; mouse; neuroscience