An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

J Biol Chem. 2016 Jun 3;291(23):12282-93. doi: 10.1074/jbc.M115.698092. Epub 2016 Apr 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Apoptosis / genetics
  • Blotting, Western
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Caspases / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Death-Associated Protein Kinases / metabolism
  • Humans
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Mutation, Missense*
  • NADPH Oxidases / metabolism
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Netrin Receptors
  • Netrin-1
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Binding
  • Protein Kinase C / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / genetics*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • CALML5 protein, human
  • Calcium-Binding Proteins
  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • UNC5C protein, human
  • Netrin-1
  • NADPH Oxidases
  • protein kinase D
  • Death-Associated Protein Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 8
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human
  • Caspases