HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation.

Autor:	Qi L; 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., Sun X; Department of Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Li FE; Department of Interventional Treatment, Tianjin Medical University Cancer Hospital and Institution, Laboratory of Cancer Prevention and Therapy, Tianjin, China., Zhu BS; Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Braun FK; 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., Liu ZQ; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America., Tang JL; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., Wu C; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., Xu F; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., Wang HH; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America., Velasquez LA; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America., Zhao K; Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Lei FR; Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Zhang JG; Department of Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Shen YT; Department of Radiotherapy Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China., Zou JX; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., Meng HM; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., An GL; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., Yang L; Hematology Center, Cyrus Tang Medical Institute, Soochow University, Suzhou, Jiangsu, China., Zhang XD; 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.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2015 Nov 13; Vol. 10 (11), pp. e0142901. Date of Electronic Publication: 2015 Nov 13 (Print Publication: 2015).
DOI:	10.1371/journal.pone.0142901
Abstrakt:	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.
Databáze:	MEDLINE
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