Thiamine deficiency induces endoplasmic reticulum stress in neurons

X. Wang, B. Wang, Z. Fan, X. Shi, Z. J. Ke, J. Luo

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Thiamine (vitamin B1) deficiency (TD) causes region selective neuronal loss in the brain; it has been used to model neurodegeneration that accompanies mild impairment of oxidative metabolism. The mechanisms for TD-induced neurodegeneration remain incompletely elucidated. Inhibition of protein glycosylation, perturbation of calcium homeostasis and reduction of disulfide bonds provoke the accumulation of unfolded proteins in the endoplasmic reticulum (ER), and cause ER stress. Recently, ER stress has been implicated in a number of neurodegenerative models. We demonstrated here that TD up-regulated several markers of ER stress, such as glucose-regulated protein (GRP) 78, growth arrest and DNA-damage inducible protein or C/EBP-homologus protein (GADD153/Chop), phosphorylation of eIF2α and cleavage of caspase-12 in the cerebellum and the thalamus of mice. Furthermore, ultrastructural analysis by electron microscopic study revealed an abnormality in ER structure. To establish an in vitro model of TD in neurons, we treated cultured cerebellar granule neurons (CGNs) with amprolium, a potent inhibitor of thiamine transport. Exposure to amprolium caused apoptosis and the generation of reactive oxygen species in CGNs. Similar to the observation in vivo, TD up-regulated markers for ER stress. Treatment of a selective inhibitor of caspase-12 significantly alleviated amprolium-induced death of CGNs. Thus, ER stress may play a role in TD-induced brain damage.

Original languageEnglish
Pages (from-to)1045-1056
Number of pages12
JournalNeuroscience
Volume144
Issue number3
DOIs
StatePublished - Feb 9 2007

Bibliographical note

Funding Information:
We would like to thank Dr. He Xu for assistance in the statistical analyses and Mr. Chun Feng for assistance in confocal laser-scanning microscopy. We also want to thank Ms. Kimberly A. Bower for reading this manuscript. This research was supported by grants from the National Natural Science Foundation of China (30470544, 30471452 and 30570580) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars that is sponsored by State Education Ministry. Dr. Z. J. Ke was also supported by One Hundred Talents Program of Chinese Academy of Sciences. Dr. X. Wang was also supported by China Postdoctoral Science Foundation and Shanghai Postdoctoral Scientific Program.

Keywords

  • cell death
  • cerebellum
  • neurodegeneration
  • nutrition
  • vitamin B1

ASJC Scopus subject areas

  • General Neuroscience

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