HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

Song, Ju‐Xian; Lu, Jiahong; Liu, Liang-Feng; Chen, Leilei; Durairajan, Siva Sundara Kumar; Yue, Zhenyu; Zhang, Hong Qi; Li, Min

doi:10.4161/auto.26751

Cited by 141 publications

(72 citation statements)

References 35 publications

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“…In response to nutrient-limiting conditions or environmental insults, the autophagy is initiated to form double-membrane autophagosomes. Then the autophagosomes mature and the unwanted proteins and damaged organelles are drived to lysosomes to form the autolysosome [17][18][19]. The researches revealed that OPIDN was associated with a significant autophagic dysfunction in hen nervous tissue.…”

Section: Introductionmentioning

confidence: 98%

RETRACTED ARTICLE: Apelin-13 Prevents the Delayed Neuropathy Induced by Tri-ortho-cresyl Phosphate Through Regulation the Autophagy Flux in Hens

et al. 2015

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Organophosphate-induced delayed neuropathy (OPIDN) is pathologically characterized by the swollen axon containing aggregations of microtubules, neurofilaments, smooth endoplasmic reticulum and multivesicular vesicles. At present, the exact mechanism of OPIDN is unclear and the effective therapeutic methods is not available to counter this syndrome. Recent studies had shown that the autophagy was involved in OPIDN. The adipocytokine Apelin is a peptide, Apelin and its receptor are abundantly expressed in the nervous system. Recent researches illuminated that Apelin was neuroprotective factor and Apelin could regulate the autophagy in vivo and vitro model. So we investigated the effect of Apelin-13 on the OPIDN induced by Tri-ortho-cresyl phosphate (TOCP) in hens and explored the role of autophagy in Apelin-13 preventing OPIDN. Adult Roman hens were given a single dose of 750 mg/kg TOCP by gavage for 21 days to induce OPIDN, and neural dysfunction were detected, and the formation of autophagosomes in spinal cord neurons was observed by transmission electron microscopy, and the molecular markers of autophagy microtubule-associated protein light chain-3 (LC3) and the autophagy substrates p62/SQSTM1 were determined by Western blot analysis. The results demonstrated that the obvious neurological dysfunction such as hindlimb paralysis and paralysis of gait was present, the number of autophagosomes in the neurons of spinal cords was significantly increased, the level of LC3-II and p62 expressions and the ratio of LC3-II/LC3-I in spinal cords and sciatic nerve were significantly increased in the OPIDN model group compared with the control group. Compared with the OPIDN model group, the neurological dysfunction of tens was obviously reduced, the clinical signs scores was significantly decreased, the number of autophagosomes in the neurons of hen spinal cords was significantly decreased, the level of LC3-II and p62 expressions and the ratio of LC3-II/LC3-I in spinal cords and sciatic nerve were significantly decreased in Apelin-13 treatment group. Our results suggested that Apelin-13 prevented against the OPIDN induced by TOCP in hens, which the mechanism might be associated with regulation autophagy flux by Apelin-13.

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Section: Introductionmentioning

confidence: 98%

RETRACTED ARTICLE: Apelin-13 Prevents the Delayed Neuropathy Induced by Tri-ortho-cresyl Phosphate Through Regulation the Autophagy Flux in Hens

et al. 2015

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“…Even though the causal involvement of autophagic processes in this protection remains to be elucidated, these results are in line with studies reporting an impairment of autophagy upon high gene doses of aSyn [52][53][54] and enhanced neuroprotection upon induction of autophagy by pharmacological and genetic means such as treatment with resveratrol, trehalose, metformin, or rapamycin or overexpression of Beclin-1 or TFEB, the major transcriptional regulator of the autophagic pathway. 43,[55][56][57][58] Altogether these studies place the fine-tuning of autophagy regulation rather than autophagy itself, which as a degradative process is not intrinsically protective, at the core of neuronal viability during PD.…”

Section: Discussionsupporting

confidence: 84%

Spermidine protects against α-synuclein neurotoxicity

et al. 2014

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These authors contributed equally to this work.Keywords: autophagy, aging, a-synuclein, dopaminergic neuron loss, motor dysfunction, neurodegeneration, Parkinson's disease, SpermidineAs our society ages, neurodegenerative disorders like Parkinson`s disease (PD) are increasing in pandemic proportions. While mechanistic understanding of PD is advancing, a treatment with well tolerable drugs is still elusive. Here, we show that administration of the naturally occurring polyamine spermidine, which declines continuously during aging in various species, alleviates a series of PD-related degenerative processes in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, two established model systems for PD pathology. In the fruit fly, simple feeding with spermidine inhibited loss of climbing activity and early organismal death upon heterologous expression of human a-synuclein, which is thought to be the principal toxic trigger of PD. In this line, administration of spermidine rescued a-synuclein-induced loss of dopaminergic neurons, a hallmark of PD, in nematodes. Alleviation of PD-related neurodegeneration by spermidine was accompanied by induction of autophagy, suggesting that this cytoprotective process may be responsible for the beneficial effects of spermidine administration.

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“…HMGB1 is identified as α-synuclein filament-binding protein and its direct interaction can inhibit HMGB1-mediated autophagy, which contributes to the neurodegenerative process (Lindersson et al, 2004; Song et al, 2014). …”

Section: Hmgb1 Receptors (Figure 7)mentioning

confidence: 99%

“…Cytosolic HMGB1 competes with Bcl-2 for interaction with Beclin-1 by intra-molecular disulfide bridge (C23/45) of HMGB1, which in turn promotes Beclin-1-mediated autophagosomes (Tang et al, 2010b). The interaction between HMGB1 and Beclin-1 is positively regulated by ULK1 (Huang et al, 2012a), MAPK (Tang et al, 2010b), and NAC (Cheng et al, 2013), but negatively regulated by p53 (Livesey et al, 2012a) and synuclein (Song et al, 2014). Extracellular HMGB1 in its reduced form promotes autophagy through binding to RAGE (Tang et al, 2010a), which may contribute to lactate production and glutamine metabolism for tumor growth (Luo et al, 2014).…”

Section: Hmgb1 and Cell Death (Figure 12)mentioning

confidence: 99%

HMGB1 in health and disease

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Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

822

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

Cited by 141 publications

References 35 publications

RETRACTED ARTICLE: Apelin-13 Prevents the Delayed Neuropathy Induced by Tri-ortho-cresyl Phosphate Through Regulation the Autophagy Flux in Hens

RETRACTED ARTICLE: Apelin-13 Prevents the Delayed Neuropathy Induced by Tri-ortho-cresyl Phosphate Through Regulation the Autophagy Flux in Hens

Spermidine protects against α-synuclein neurotoxicity

HMGB1 in health and disease

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