机构：[1]Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China,[2]Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America,[3]Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States of America,[4]Department of Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China,[5]Department of Interventional Treatment, Tianjin Medical University Cancer Hospital and Institution, Laboratory of Cancer Prevention and Therapy, Tianjin, China,[6]Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China,[7]Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China,[8]Department of Radiotherapy Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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.
基金：
This work was supported by The MD
Anderson Cancer Center SPORE in Multiple
Myeloma (5P50CA142509-04), by the Priority
Academic Program Development of Jiangsu Higher
Education Institutions of China, by the National
Natural Science Foundation of China (Nos.
81201861, 31471283 and 81101909), by the
Postdoctoral Science Foundation of China
(2011M500949), and by the Multiple Myeloma
Research Foundation 2013 Research Fellow Award
(to X-D Zhang).
第一作者机构：[1]Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China,[3]Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States of America,
共同第一作者：
通讯作者：
通讯机构：[1]Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China,[2]Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America,
推荐引用方式(GB/T 7714)：
Lin Qi,Xue Sun,Feng-E Li,et al.HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation[J].PLOS ONE.2015,10(11):e0142901.doi:10.1371/journal.pone.0142901.
APA：
Lin Qi,Xue Sun,Feng-E Li,Bao-Song Zhu,Frank K. Braun...&Xing-Ding Zhang.(2015).HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation.PLOS ONE,10,(11)
MLA：
Lin Qi,et al."HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation".PLOS ONE 10..11(2015):e0142901
