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

Lin Qi,Lin Yang,Fei Xu,Xue Sun,Kui Zhao,Chao Wu,Ji Gang Zhang ,Hui Han Wang ,Hui Meng ,Jian Xuan Zou ,Lei Feng ,Jessica Tang ,Gang Li An ,Zhi Qiang Liu ,Bao‐Song Zhu ,Feng E Li ,Frank Braun ,Luís Velásquez ,Yun Shen ,Xingding Zhang

doi:10.1371/journal.pone.0142901

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.

Highlights

Exposure to 3-nitropropionic acid (3-NP), an irreversible inactivator of succinate dehydrogenase, induces striatal neural damage in the caudate/putamen
The results of this study suggest that mitochondrial dysfunction induced by 3-NP triggers a mixed form of cell death involving apoptosis, autophagy, and necrosis
Suppressing highmobility group box 1 (HMGB1) blocked/reduced 3-NP–induced LC3-II activation, SQSTM1 degradation, and striatal cell death, whereas exogenous of HMGB1 treatment activated autophagy and apoptosis, where much stronger when combined with 3-NP The decrease in LC3-II and increase in SQSTM1 after HMGB1 knockdown further underscores a prominent role for HMGB1 basal autophagy signaling

Summary

Introduction

Exposure to 3-nitropropionic acid (3-NP), an irreversible inactivator of succinate dehydrogenase, induces striatal neural damage in the caudate/putamen. This was shown in humans as well as in animal experiments [1,2]. Increasing evidence points to a complex interplay between autophagy and apoptotic cell death signaling mediated by 3-NP [4,5]. High-mobility group box 1 (HMGB1) protein is a chromatin-binding nuclear protein that is part of a damage-associated molecular pattern and is important for oxidative stress response as well as for cell death signaling, including autophagy and apoptosis. We investigated, in primary striatal neurons and in rats, the impact of HMGB1 on autophagy and cell death signaling under metabolic stress conditions (3-NP). We show that elevated levels of HMGB1 have a neuroprotective capacity that might be relevant for novel therapeutic approaches in neurodegenerative diseases

Materials and Methods

Findings

Discussion