title: HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation.
abstract: Impairments in mitochondrial energy metabolism are thought to be involved in many neurodegenerative diseases. The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces striatal pathology mimicking neurodegeneration in vivo. Previous studies showed that 3-NP also triggered autophagy activation and apoptosis. In this study, we focused on the high-mobility group box 1 (HMGB1) protein, which is important in oxidative stress signaling as well as in autophagy and apoptosis, to explore whether the mechanisms of autophagy and apoptosis in neurodegenerative diseases are associated with metabolic impairment. To elucidate the role of HMGB1 in striatal degeneration, we investigated the impact of HMGB1 on autophagy activation and cell death induced by 3-NP. We intoxicated rat striata with 3-NP by stereotaxic injection and analyzed changes in expression HMGB1, proapoptotic proteins caspase-3 and phospho-c-Jun amino-terminal kinases (p-JNK). 3-NP-induced elevations in p-JNK, cleaved caspase-3, and autophagic marker LC3-II as well as reduction in SQSTM1 (p62), were significantly reduced by the HMGB1 inhibitor glycyrrhizin. Glycyrrhizin also significantly inhibited 3-NP-induced striatal damage. Neuronal death was replicated by exposing primary striatal neurons in culture to 3-NP. It was clear that HMGB1 was important for basal autophagy which was shown by rescue of cells through HMGB1 targeting shRNA approach.3-NP also induced the expression of HMGB1, p-JNK, and LC3-II in striatal neurons, and p-JNK expression was significantly reduced by shRNA knockdown of HMGB1, an effect that was reversed by exogenously increased expression of HMGB1. These results suggest that HMGB1 plays important roles in signaling for both autophagy and apoptosis in neurodegeneration induced by mitochondrial dysfunction.
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.|Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Interventional Treatment, Tianjin Medical University Cancer Hospital and Institution, Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Feng-E
authors.initials: FE
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Bao-Song
authors.initials: BS
authors.lastname: Zhu
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.|Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Frank K
authors.initials: FK
authors.lastname: Braun
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Jin-Le
authors.initials: JL
authors.lastname: Tang
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wu
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Hui-Han
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Velasquez
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Feng-Rui
authors.initials: FR
authors.lastname: Lei
authors.affiliation: Department of Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yun-Tian
authors.initials: YT
authors.lastname: Shen
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Jian-Xuan
authors.initials: JX
authors.lastname: Zou
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Meng
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Gang-Li
authors.initials: GL
authors.lastname: An
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China.|Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Xing-Ding
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D019695:Glycyrrhizic Acid / Q000737:chemistry; D024243:HMGB1 Protein / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000378:metabolism; D016086:Lentivirus; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009574:Nitro Compounds / Q000737:chemistry; D018384:Oxidative Stress; D011422:Propionates / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006360:Heat-Shock Proteins; D009574:Nitro Compounds; D011422:Propionates; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; D019695:Glycyrrhizic Acid; D048670:MAP Kinase Kinase 4; C505410:Casp3 protein, rat; D053148:Caspase 3; C015392:3-nitropropionic acid