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.

HMGB1 Mediates Autophagy Dysfunction via Perturbing Beclin1-Vps34 Complex in Dopaminergic Cell Model

“…Nevertheless, overexpression of Beclin1 could instead restore autophagy, promote α-synuclein clearance (Song et al, 2014 ) and ultimately break the vicious cycle shown in Figure 7 . Moreover, HMGB1 inhibitor glycyrrhizin pretreatment or HMGB1 knockdown had also been proven to facilitate the autophagy flux and rescue 3-nitropropionic acid induced striatal damage (Qi et al, 2015 ), which is precisely consistent with the study results. In conclusion, this study has identified that HMGB1 have a higher affinity for Beclin1 and thereby perturb the Beclin1-Vps34 complex formation, thus resulting in subsequent autophagy dysfunction and α-synuclein accumulation.…”

Acupuncture as a multifunctional neuroprotective therapy ameliorates cognitive impairment in a rat model of vascular dementia: A quantitative iTRAQ proteomics study

“…HMGB1 is important for oxidative stress response and cell death signaling. HMGB1 has been shown to play an important role in signaling for mitochondrial dysfunction‐induced apoptosis . Ding et al reported that the HMGB1 together with its receptor Toll‐like receptor 4 plays a significant role in the pathogenesis of ischemic‐reperfusion injury and can induce apoptosis .…”

Role of ROS and RNS Sources in Physiological and Pathological Conditions

“…The high mobility group box 1 protein is a chromatin binding protein that recognizes DNA damage and promotes binding to p53 to stimulate an oxidative stress response, namely, autophagy or apoptosis. Studies investigating the correlation of HMGB-1 and mitochondrial dysfunction in 3-nitropropionic acid treated animals have been conducted to study the role HGMB-1 may have on striatal neurodegeneration in vivo and in vitro [ 545 ]. They demonstrated that HMGB-1 binds to beclin-1 to regulate autophagy, thereby establishing a new mechanism to study in striatal neurodegeneration via autophagy and apoptosis.…”