Activation of double-stranded RNA-activated protein kinase by mild impairment of oxidative metabolism in neurons

Xin Wang; Zhiqin Fan; Bingwei Wang; Jia Luo; Zun-Ji Ke

doi:10.1111/j.1471-4159.2007.04978.x

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Activation of double-stranded RNA-activated protein kinase by mild impairment of oxidative metabolism in neurons

Journal article

Peer reviewed

Activation of double-stranded RNA-activated protein kinase by mild impairment of oxidative metabolism in neurons

Xin Wang, Zhiqin Fan, Bingwei Wang, Jia Luo and Zun-Ji Ke

Journal of neurochemistry, Vol.103(6), pp.2380-2390

12/2007

DOI: 10.1111/j.1471-4159.2007.04978.x

PMID: 17953670

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Abstract

Thiamine (vitamin B1) deficiency (TD) causes mild and chronic impairment of oxidative metabolism and induces neuronal death in specific brain regions. The mechanisms underlying TD-induced cell death, however, remain unclear. The double-stranded RNA-activated protein kinase (PKR), has been well known for its anti-viral function. Upon activation by viral infection or double-stranded RNA, PKR phosphorylates its substrate, the alpha-subunit of eukaryotic initiation factor-2 (eIF2alpha), leading to inhibition of translation. In response to various cellular stresses, PKR can also be stimulated by its protein activators, or its mouse homologue, PKR activator (RAX). We demonstrated that TD in mice induced phosphorylation of PKR at Thr446 and Thr451 and phosphorylation of eIF2alpha at Ser51 in the cerebellum and the thalamus. TD caused phosphorylation of PKR and eIF2alpha, as well as nuclear translocation of PKR in primary cultures of cerebellar granule neurons. PKR phosphorylation is necessary for its nuclear translocation because TD failed to induce nuclear translocation of a T446A/T451A PKR mutant. Both PKR inhibitor and dominant-negative PKR mutant protected cerebellar granule neurons against TD-induced cell death. TD promoted the association between RAX and PKR. Antioxidant vitamin E dramatically decreased the RAX/PKR association and ameliorated TD-induced cell death. Our results indicate that TD-induced neuronal death is at least partially mediated by the activation of PKR.

Phosphorylation

Active Transport, Cell Nucleus - drug effects

Active Transport, Cell Nucleus - physiology

Animals

Animals, Newborn

Antioxidants - metabolism

Antioxidants - pharmacology

Brain - metabolism

Brain - physiopathology

Cells, Cultured

eIF-2 Kinase - genetics

eIF-2 Kinase - metabolism

Enzyme Activation - physiology

Eukaryotic Initiation Factor-2 - metabolism

Male

Mice

Mice, Inbred C57BL

Nerve Degeneration - etiology

Nerve Degeneration - metabolism

Nerve Degeneration - physiopathology

Neurons - metabolism

Oxidative Phosphorylation

Oxidative Stress - physiology

Rats

Rats, Sprague-Dawley

Serine - metabolism

Thiamine Deficiency - metabolism

Thiamine Deficiency - physiopathology

Threonine - metabolism

Tocopherols - metabolism

Tocopherols - pharmacology

Details

Title: Subtitle: Activation of double-stranded RNA-activated protein kinase by mild impairment of oxidative metabolism in neurons
Creators: Xin Wang - Chinese Academy of Sciences
Zhiqin Fan - Chinese Academy of Sciences
Bingwei Wang - Chinese Academy of Sciences
Jia Luo - West Virginia University
Zun-Ji Ke
Resource Type: Journal article
Publication Details: Journal of neurochemistry, Vol.103(6), pp.2380-2390
DOI: 10.1111/j.1471-4159.2007.04978.x
PMID: 17953670
ISSN: 0022-3042
eISSN: 1471-4159
Grant note: AA015407 / NIAAA NIH HHS R01 AA015407 / NIAAA NIH HHS R21 AA013984 / NIAAA NIH HHS
Language: English
Date published: 12/2007
Academic Unit: Pathology
Record Identifier: 9984186577902771

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