Abstract

Potassium (K(+)) channels are essential to neuronal signaling and survival. Here we show that these proteins are targets of reactive oxygen species in mammalian brain and that their oxidation contributes to neuropathy. Thus, the KCNB1 (Kv2.1) channel, which is abundantly expressed in cortex and hippocampus, formed oligomers upon exposure to oxidizing agents. These oligomers were ∼10-fold more abundant in the brain of old than young mice. Oxidant-induced oligomerization of wild-type KCNB1 enhanced apoptosis in neuronal cells subject to oxidative insults. Consequently, a KCNB1 variant resistant to oxidation, obtained by mutating a conserved cysteine to alanine, (C73A), was neuroprotective. The fact that oxidation of KCNB1 is toxic, argues that this mechanism may contribute to neuropathy in conditions characterized by high levels of oxidative stress, such as Alzheimer's disease (AD). Accordingly, oxidation of KCNB1 channels was exacerbated in the brain of a triple transgenic mouse model of AD (3xTg-AD). The C73A variant protected neuronal cells from apoptosis induced by incubation with β-amyloid peptide (Aβ(1-42)). In an invertebrate model (Caenorhabditis elegans) that mimics aspects of AD, a C73A-KCNB1 homolog (C113S-KVS-1) protected specific neurons from apoptotic death induced by ectopic expression of human Aβ(1-42). Together, these data underscore a novel mechanism of toxicity in neurodegenerative disease.

Links

Publisher Full Text

Authors

Cotella D, Hernandez-Enriquez B, Wu X, Li R, Pan Z, Leveille J, Link CD, Oddo S, Sesti F

Institution

Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.

Source

The Journal of neuroscience : the official journal of the Society for Neuroscience 32:12 2012 Mar 21 pg 4133-44

MeSH

2,2'-Dipyridyl
Age Factors
Alanine
Alzheimer Disease
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Analysis of Variance
Animals
Animals, Genetically Modified
Apoptosis
Brain
Caenorhabditis elegans
Cells, Cultured
Cricetinae
Cricetulus
Cysteine
Disease Models, Animal
Disulfides
Electric Stimulation
Embryo, Mammalian
Female
Fluoresceins
Humans
Hydrogen Peroxide
Male
Mass Spectrometry
Membrane Potentials
Mice
Neurons
Oxidants
Oxidation-Reduction
Oxidative Stress
Patch-Clamp Techniques
Peptide Fragments
Presenilin-1
Propanols
Shab Potassium Channels
Transfection

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22442077