RRC ID 46052
Author Cotella D, Hernandez-Enriquez B, Wu X, Li R, Pan Z, Leveille J, Link CD, Oddo S, Sesti F.
Title Toxic role of K+ channel oxidation in mammalian brain.
Journal J Neurosci
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.
Volume 32(12)
Pages 4133-44
Published 2012-3-21
DOI 10.1523/JNEUROSCI.6153-11.2012
PII 32/12/4133
PMID 22442077
PMC PMC6621216
MeSH 2,2'-Dipyridyl / analogs & derivatives 2,2'-Dipyridyl / toxicity Age Factors Alanine / genetics Alzheimer Disease / genetics Alzheimer Disease / pathology Alzheimer Disease / physiopathology Amyloid beta-Peptides / toxicity Amyloid beta-Protein Precursor / genetics Analysis of Variance Animals Animals, Genetically Modified Apoptosis / drug effects Apoptosis / genetics Apoptosis / physiology Brain / cytology* Caenorhabditis elegans Cells, Cultured Cricetinae Cricetulus Cysteine / genetics Disease Models, Animal Disulfides / toxicity Electric Stimulation Embryo, Mammalian Female Fluoresceins / pharmacology Humans Hydrogen Peroxide / pharmacology Male Mass Spectrometry / methods Membrane Potentials / genetics Membrane Potentials / physiology Mice Neurons / drug effects Neurons / physiology* Oxidants / toxicity Oxidation-Reduction / drug effects Oxidative Stress / drug effects Oxidative Stress / genetics Oxidative Stress / physiology* Patch-Clamp Techniques Peptide Fragments / toxicity Presenilin-1 / genetics Propanols / pharmacology Shab Potassium Channels / genetics Shab Potassium Channels / physiology* Transfection
IF 6.074
Times Cited 45
C.elegans tm2034