title: HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression: a process modulated by the natural autophagy inducer corynoxine B.
abstract: SNCA/α-synuclein and its rare mutations are considered as the culprit proteins in Parkinson disease (PD). Wild-type (WT) SNCA 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 SNCA(A53T) inhibits autophagy in PC12 cells in a time-dependent manner. Furthermore, we showed that SNCA binds to both cytosolic and nuclear high mobility group box 1 (HMGB1), impairs the cytosolic translocation of HMGB1, blocks HMGB1-BECN1 binding, and strengthens BECN1-BCL2 binding. Deregulation of these molecular events by SNCA overexpression leads to autophagy inhibition. Overexpression of BECN1 restores autophagy and promotes the clearance of SNCA. siRNA knockdown of Hmgb1 inhibits basal autophagy and abolishes the inhibitory effect of SNCA 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 SNCA, which may be attributed to its ability to block SNCA-HMGB1 interaction. Based on these findings, we propose that SNCA-induced impairment of autophagy occurs, in part, through HMGB1, which may provide a potential therapeutic target for PD.
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong.
authors.forename: Ju-Xian
authors.initials: JX
authors.lastname: Song
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong; Departments of Neurology and Neuroscience; Friedman Brain Institute; Icahn School of Medicine at Mount Sinai; New York, NY USA.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Lu
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong.
authors.forename: Liang-Feng
authors.initials: LF
authors.lastname: Liu
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Chen
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong.
authors.forename: Siva Sundara Kumar
authors.initials: SS
authors.lastname: Durairajan
authors.affiliation: Departments of Neurology and Neuroscience; Friedman Brain Institute; Icahn School of Medicine at Mount Sinai; New York, NY USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong.
authors.forename: Hong-Qi
authors.initials: HQ
authors.lastname: Zhang
authors.affiliation: School of Chinese Medicine; Hong Kong Baptist University; Kowloon Tong; Hong Kong.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002470:Cell Survival; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D026121:Indole Alkaloids; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013997:Time Factors; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D024243:HMGB1 Protein; D026121:Indole Alkaloids; D050505:Mutant Proteins; D051844:alpha-Synuclein; C054799:corynoxeine; D046988:Proteasome Endopeptidase Complex
keywords: HMGB1; Parkinson disease; SNCA; autophagy; corynoxine B