title: An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.
abstract: A missense mutation (T835M) in the uncoordinated-5C (UNC5C) netrin receptor gene increases the risk of late-onset Alzheimer disease (AD) and also the vulnerability of neurons harboring the mutation to various insults. The molecular mechanisms underlying T835M-UNC5C-induced death remain to be elucidated. In this study, we show that overexpression of wild-type UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M. An AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1, inhibit this death. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of death-associated protein kinase 1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid β precursor protein (APP). Notably, netrin1 also binds to APP and partially inhibits the death-signaling cascade, induced by APP. These results may provide new insight into the amyloid β-independent pathomechanism of AD.
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusakari
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Mikiro
authors.initials: M
authors.lastname: Nawa
authors.affiliation: From the Departments of Pharmacology and Dermatological Neuroscience, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan sakimatu@tokyo-med.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000378:metabolism; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C408467:CALML5 protein, human; D002135:Calcium-Binding Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C115727:UNC5C protein, human; D000075388:Netrin-1; D019255:NADPH Oxidases; C089212:protein kinase D; D064550:Death-Associated Protein Kinases; D011493:Protein Kinase C; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D020169:Caspases
keywords: Alzheimer disease; UNC5C; amyloid beta-independent; amyloid precursor protein (APP); apoptosis; neurodegenerative disease; neuronal cell death; signal transduction