title: Presenilin-1 influences processing of the acetylcholinesterase membrane anchor PRiMA.
abstract: Presenilin-1 (PS1) is the catalytic component of the γ-secretase complex. In this study, we explore if PS1 participates in the processing of the cholinergic acetylcholinesterase (AChE). The major AChE variant expressed in the brain is a tetramer (G(4)) bound to a proline-rich membrane anchor (PRiMA). Overexpression of the transmembrane PRiMA protein in Chinese hamster ovary cells expressing AChE and treated with the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester have enabled us to study whether, through its γ-secretase activity, PS1 participates in the processing of PRiMA-linked AChE. γ-Secretase inhibition led to a notable increase in the level of PRiMA-linked AChE, suggesting that γ-secretase is involved in the cleavage of PRiMA. We demonstrate that cleavage of PRiMA by γ-secretase results in a C-terminal PRiMA fragment. Immunofluorescence labeling allowed us to identify this PRiMA fragment in the nucleus. Moreover, we have determined changes in the proportion of the raft-residing AChE-PRiMA in a PS1 conditional knockout mouse. Our results are of interest as both enzymes have therapeutic relevance for Alzheimer's disease.
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (CSIC), Sant Joan d'Alacant, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Unidad de Investigación, Hospital General Universitario de Elche, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Elche, Spain.
authors.forename: María-Salud
authors.initials: MS
authors.lastname: García-Ayllón
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (CSIC), Sant Joan d'Alacant, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: María-Letizia
authors.initials: ML
authors.lastname: Campanari
authors.affiliation: Departamento de Bioquímica y Biología Molecular-A, Universidad de Murcia, Regional Campus of International Excellence "Campus Mare Nostrum", Murcia, Spain.
authors.forename: María-Fernanda
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (CSIC), Sant Joan d'Alacant, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Cuchillo-Ibáñez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China.
authors.forename: Karl
authors.initials: K
authors.lastname: Tsim
authors.affiliation: Departamento de Bioquímica y Biología Molecular-A, Universidad de Murcia, Regional Campus of International Excellence "Campus Mare Nostrum", Murcia, Spain.
authors.forename: Cecilio J
authors.initials: CJ
authors.lastname: Vidal
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (CSIC), Sant Joan d'Alacant, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: j.saez@umh.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Sáez-Valero
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D006224:Cricetinae; D015195:Drug Design; D005260:Female; D015870:Gene Expression / Q000235:genetics; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D053764:Presenilin-1 / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; C486718:prima1 protein, mouse; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases
keywords: Acetylcholinesterase; Alzheimer's disease; PRiMA; Presenilin 1; γ-Secretase