title: Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via γ-secretase-independent transcriptional mechanisms.
abstract: Epidermal growth factor receptor (EGFR) plays pivotal roles in cell proliferation, differentiation, and tissue development, while EGFs protect neurons from toxic insults by binding EGFR and stimulating survival signaling. Furthermore, recent evidence implicates this receptor in neurometabolic disorders like Alzheimer disease and aging. Here we show that absence of presenilin 1 (PS1) results in dramatic decrease (>95%) of neuronal EGFR and that PS1-null (PS1(-/-)) brains have reduced amounts of this receptor. PS1(-/-) cortical neurons contain little EGFR and show no epidermal growth factor-induced survival signaling or protection against excitotoxicity, but exogenous EGFR rescues both functions even in absence of PS1. EGFR mRNA is greatly reduced (>95%) in PS1(-/-) neurons, and PS1(-/-) brains contain decreased amounts of this mRNA, although PS1 affects the stability of neither EGFR nor its mRNA. Exogenous PS1 increases neuronal EGFR mRNA, while down-regulation of PS1 decreases this mRNA. These effects are neuron specific, as PS1 affects the EGFR of neither glial nor fibroblast cells. In addition, PS1 controls EGFR through novel mechanisms shared with neither γ-secretase nor PS2. Our data reveal that PS1 functions as a positive transcriptional regulator of neuronal EGFR controlling its expression in a cell-specific manner. Severe downregulation of EGFR may contribute to developmental abnormalities and lethal phenotype found in PS1, but not PS2, null mice. Furthermore, PS1 may affect neuroprotection and Alzheimer disease by controlling survival signaling of neuronal EGFR.
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Bruban
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Voloudakis
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kajiwara
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Md
authors.initials: M
authors.lastname: Al Rahim
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Yonejung
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Shioi
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gama Sosa
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Shao
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.affiliation: *Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York, USA; School of Medicine, University of Crete, Heraklion, Crete, Greece; and James J. Peters Department of Veterans Affairs Medical Center, General Medical Research Service, Bronx, New York, USA nikos.robakis@mssm.edu.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D053764:Presenilin-1; C580804:presenilin 1, mouse; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer disease; EGFR mRNA; neurodegeneration; survival signaling