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.
Keywords:
Alzheimer disease; UNC5C; amyloid beta-independent; amyloid precursor protein (APP); apoptosis; neurodegenerative disease; neuronal cell death; signal transduction.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Amyloid beta-Protein Precursor / genetics*
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Apoptosis / genetics
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Blotting, Western
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Caspases / metabolism
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Cell Line
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Cell Line, Tumor
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Death-Associated Protein Kinases / metabolism
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Humans
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism
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Mitogen-Activated Protein Kinase 8 / metabolism
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Mutation, Missense*
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NADPH Oxidases / metabolism
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Netrin Receptors
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Netrin-1
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Neurons / cytology
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Neurons / metabolism
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Protein Binding
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Protein Kinase C / metabolism
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / metabolism
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Signal Transduction / genetics*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Amyloid beta-Protein Precursor
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CALML5 protein, human
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Calcium-Binding Proteins
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NTN1 protein, human
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Nerve Growth Factors
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Netrin Receptors
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Receptors, Cell Surface
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Tumor Suppressor Proteins
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UNC5C protein, human
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Netrin-1
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NADPH Oxidases
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protein kinase D
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Death-Associated Protein Kinases
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Protein Kinase C
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Mitogen-Activated Protein Kinase 8
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MAP Kinase Kinase Kinase 5
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MAP3K5 protein, human
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Caspases