HMGB1 is involved in autophagy inhibition caused by SNCA/a-synuclein overexpression :A process modulated by the natural autophagy inducer corynoxine B

Juxian SONG, Jia Hong Lu, Liangfeng LIU, Lei Lei Chen, S S Kumar DURAIRAJAN, Zhenyu Yue, Hong Qi ZHANG*, Min LI

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)

Abstract

SNC A/a-synuclein and its rare mutations are considered as the culprit proteins in Parkinson disease (PD). Wild-type (WT) SNC A has been shown to impair macroautophagy in mammalian cells and in transgenic mice. In this study, we monitored the dynamic changes in autophagy process and confirmed that overexpression of both WT and SNC AA53T inhibits autophagy in PC12 cells in a time-dependent manner. Furthermore, we showed that SNC A binds to both cytosolic and nuclear high mobility group box 1 (HMGB1), impairs the cytosolic translocation of HMGB1, blocks HMGB1- BECN 1 binding, and strengthens BECN 1-BCL2 binding. Deregulation of these molecular events by SNC A overexpression leads to autophagy inhibition. Overexpression of BECN 1 restores autophagy and promotes the clearance of SNC A. siRN A knockdown of Hmgb1 inhibits basal autophagy and abolishes the inhibitory effect of SNC A on autophagy while overexpression of HMGB1 restores autophagy. Corynoxine B, a natural autophagy inducer, restores the deficient cytosolic translocation of HMGB1 and autophagy in cells overexpressing SNC A, which may be attributed to its ability to block SNC A-HMGB1 interaction. Based on these findings, we propose that SNC A-induced impairment of autophagy occurs, in part, through HMGB1, which may provide a potential therapeutic target for PD.

Original languageEnglish
Pages (from-to)144-154
Number of pages11
JournalAutophagy
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 2014

Scopus Subject Areas

  • Molecular Biology
  • Cell Biology

User-Defined Keywords

  • Autophagy
  • Corynoxine B
  • HMGB1
  • Parkinson disease
  • SNCA

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