Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Liu, Chang; Yan, Dong-Ying; Tan, Xuan; Ma, Zhuo; Wang, Can; Deng, Yu; Liu, Wei; Yang, Tianyao; Xu, Zhenbo; Xu, Bin

doi:10.1002/tox.22518

Cited by 22 publications

(14 citation statements)

References 26 publications

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“…Interestingly, 4-PBA treatment increased the levels of UCHL1 in the diabetic rat brain. 42 Nevertheless, in line with the earlier studies, 43 4-PBA has no effect on ER stress markers in healthy (control) rats. 4-PBA interacts with hydrophobic domains of misfolded proteins and, thus, prevents their aggregation.…”

Section: Discussionsupporting

confidence: 80%

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Karnam

Reddy

Chitra

2018

J of Cellular Biochemistry

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The ubiquitin‐proteasome system (UPS) has been implicated in the pathogenesis of many neurodegenerative diseases. Endoplasmic reticulum (ER) stress is shown to play a pathological role in the development of diabetes and its complications. Hence, the current study is aimed to investigate the role of UPS and ER stress in the cerebral cortex of diabetic rats and examine the therapeutic effect of 4‐phenylbutyric acid (4‐PBA), an ER stress inhibitor. Male Sprague‐Dawley rats were divided into three groups: control, diabetes, and diabetes plus 4‐PBA treatment group. Diabetes was induced by single intraperitoneal streptozotocin injection (37 mg/kg body weight [bw]), and 4‐PBA was administered (40 mg/kg bw/d, intraperitoneal) for 2 months, starting from 2 months of diabetes induction. At the end of 4 months, cerebral cortex was collected for analysis. Declined proteasome activity and ubiquitin C‐terminal hydrolase (UCH)‐L1 expression, increased ubiquitinated proteins, and apoptosis were observed in the diabetic rats. The expression of the ubiquitin‐activating enzyme E1, UCHL5, and ER stress markers (ATF6, pPERK, and CHOP) was markedly elevated, whereas the expression of ER‐associated protein degradation (ERAD) components was downregulated in the diabetic rats. 4‐PBA intervention attenuated ER stress, alterations in UPS, and ERAD components in diabetic rats. Importantly, neuronal apoptosis was lowered in 4‐PBA‐treated diabetic rats. Our observations demonstrate that altered UPS could be one of the underlying mechanisms of neuronal apoptosis in diabetes and chemical chaperones such as 4‐PBA could be potential candidates for preventing these alterations under hyperglycemic conditions.

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Section: Discussionsupporting

confidence: 80%

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Karnam

Reddy

Chitra

2018

J of Cellular Biochemistry

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“…Our results suggest that oral administration of TiO 2 NPs initially induces ER stress followed by ROS generation, and finally, IR and elevation of plasma glucose, signifying that ER stress is not induced by ROS. The chemical chaperone, 4‐PBA, relieves ER stress but cannot directly affect ROS generation . In our experiments, 4‐PBA effectively inhibited TiO 2 NP‐induced ER stress as well as ROS production and plasma glucose levels in mice in vivo and mouse NIH/3T3 cells in vitro.…”

Section: Discussionmentioning

confidence: 54%

“…The chemical chaperone, 4-PBA, relieves ER stress but cannot directly affect ROS generation. 31,32 In our experiments, 4-PBA effectively inhibited TiO 2 NP-induced ER stress as well as ROS production and plasma glucose levels in mice in vivo and mouse NIH/3T3 cells in vitro. Based on the collective findings, we propose that TiO 2 NPinduced ER stress contributes to ROS generation and plays a key role in mediating plasma glucose levels in mice.…”

Section: Tio 2 Nps Induce Insulin Resistance and Elevation Of Plasmmentioning

confidence: 50%

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Fan

Yao

et al. 2019

Environmental Toxicology

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Titanium dioxide nanoparticles (TiO2 NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO2 NPs but the underlying mechanisms are unclear at present. Data from genome‐wide analyses showed that TiO2 NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO2 NP‐induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO2 NP‐induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO2 NP‐induced ER stress occurred earlier than ROS generation. Upon treatment with 4‐phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO2 NP increased ROS production was inhibited. These results suggest that TiO2 NP‐induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO2 NPs on plasma glucose metabolism.

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“…Similarly, miR‐138‐5p was proved to suppress autophagy in pancreatic cancer as well . As mentioned above, autophagy is an important way to remove misfolded or dysfunctional proteins or organelles for cells, and its inhibition could aggravate neuronal cell damage . Therefore, there is a reason to consider that miR‐138‐5p plays a key role in the neurotoxicity of Mn by retarding Mn‐induced autophagy.…”

Section: Discussionmentioning

confidence: 96%

“…In addition, the α‐synuclein oligomerization was reduced by autophagy activator rapamycin and increased by autophagy inhibitor 3‐MA, which indicated that activation of autophagy attenuated neuronal cell damage induced by MnCl 2. Another Mn poisoning model of rat also suggested that the protection of autophagy induced by MnCl 2 after a single intrastriatal injection of Mn for short‐term (4‐12 hours). However, the protection disappeared with intrastriatal injection of Mn for long‐term (1‐28 days) excessive exposure to Mn, which demonstrated that autophagy plays a protective role against Mn‐induced neuronal damage, while dysregulation of autophagy at later phases mediates DAergic neurodegeneration.…”

Section: Discussionmentioning

confidence: 98%

Overexpression of miR‐138‐5p suppresses MnCl₂‐induced autophagy by targeting SIRT1 in SH‐SY5Y cells

Zhang

et al. 2019

Environmental Toxicology

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The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl 2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl 2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3 0 -UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl 2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1. K E Y W O R D S autophagy, manganese, MicroRNA-138-5p, SIRT1

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Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Cited by 22 publications

References 26 publications

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Overexpression of miR‐138‐5p suppresses MnCl₂‐induced autophagy by targeting SIRT1 in SH‐SY5Y cells

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Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Cited by 22 publications

References 26 publications

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Overexpression of miR‐138‐5p suppresses MnCl2‐induced autophagy by targeting SIRT1 in SH‐SY5Y cells

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Overexpression of miR‐138‐5p suppresses MnCl₂‐induced autophagy by targeting SIRT1 in SH‐SY5Y cells