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Protein aggregation in neurons following OGD: a role for Na + and Ca 2+ ionic dysregulation
Author(s) -
Chen Xinzhi,
Kintner Douglas B.,
Baba Akemichi,
Matsuda Toshio,
Shull Gary E.,
Sun Dandan
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06438.x
Subject(s) - proteasome , chemistry , ubiquitin , endoplasmic reticulum , homeostasis , protein degradation , intracellular , protein aggregation , microbiology and biotechnology , biochemistry , biophysics , biology , gene
J. Neurochem. (2010) 112 , 173–182. Abstract In this study, we investigated whether disruption of Na + and Ca 2+ homeostasis via activation of Na + ‐K + ‐Cl − cotransporter isoform 1 (NKCC1) and reversal of Na + /Ca 2+ exchange (NCX rev ) affects protein aggregation and degradation following oxygen–glucose deprivation (OGD). Cultured cortical neurons were subjected to 2 h OGD and 1–24 h reoxygenation (REOX). Redistribution of ubiquitin and formation of ubiquitin‐conjugated protein aggregates occurred in neurons as early as 2 h REOX. The protein aggregation progressed further by 8 h REOX. There was no significant recovery at 24 h REOX. Moreover, the proteasome activity in neurons was inhibited by 80–90% during 2–8 h REOX and recovered partially at 24 h REOX. Interestingly, pharmacological inhibition or genetic ablation of NKCC1 activity significantly decreased accumulation of ubiquitin‐conjugated protein aggregates and improved proteasome activity. A similar protective effect was obtained by blocking NCX rev activity. Inhibition of NKCC1 activity also preserved intracellular ATP and Na + homeostasis during 0–24 h REOX. In a positive control study, disruption of endoplasmic reticulum Ca 2+ with thapsigargin triggered redistribution of free ubiquitin and protein aggregation. We conclude that overstimulation of NKCC1 and NCX rev following OGD/REOX partially contributes to protein aggregation and proteasome dysfunction as a result of ionic dysregulation.