An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid ß Precursor Protein Signaling.
J Biol Chem
; 291(23): 12282-93, 2016 Jun 03.
Article
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| MEDLINE
| ID: mdl-27068745
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 ß 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 ß-independent pathomechanism of AD.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Precursor de Proteína beta-Amiloide
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Receptores de Superficie Celular
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Mutación Missense
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Enfermedad de Alzheimer
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2016
Tipo del documento:
Article