title: DISC1 regulates trafficking and processing of APP and Aβ generation.
abstract: We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal-secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of amyloid beta (Aβ)42 and Aβ40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aβ42 and Aβ40 levels. Finally, we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aβ peptide generation, which is central to Alzheimer's disease pathology, suggests a novel interface between neurological and psychiatric conditions.
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Shahani
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jaaro-Peled
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ishizuka
authors.affiliation: Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota-Tsuyada
authors.affiliation: Neuroscience Research Unit, Pfizer, Groton, CT, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Koga
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Sedlak
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Korth
authors.affiliation: Neuroscience Research Unit, Pfizer, Groton, CT, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tomoda
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; C498794:Disc1 protein, mouse; C498795:Disc1 protein, rat; D009419:Nerve Tissue Proteins