DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes

Chen, Rui; Wang, Bin; Chen, Ling; Cai, Dunpeng; Li, Bing; Chen, Chuanxiang; Huang, Enping; Liu, Chao; Lin, Zhoumeng; Xie, Wei‐Bing; Wang, Huijun

doi:10.1016/j.taap.2016.01.017

Cited by 50 publications

(36 citation statements)

References 41 publications

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“…ER stress can upregulate the Nupr1/Trib3 pathway and then induce autophagy by inhibiting the AKT/mTORC1 axis (Salazar et al, 2009). In addition, phosphorylation of mTOR (p-mTOR) also plays an important role in cell autophagy (Meijer and Codogno, 2006; Chen R. et al, 2016). AKT, also known as protein kinase B, plays a critical role in controlling cell survival and apoptosis (Franke et al, 1997; Kandel and Hay, 1999).…”

Section: Resultsmentioning

confidence: 99%

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Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Huang

Tai

et al. 2017

Front. Mol. Neurosci.

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Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH exposure causes detrimental effects on multiple organ systems, primarily the nervous system, especially dopaminergic pathways, in both laboratory animals and humans. In this study, we hypothesized that Nuclear protein 1 (Nupr1/com1/p8) is involved in METH-induced neuronal apoptosis and autophagy through endoplasmic reticulum (ER) stress signaling pathway. To test this hypothesis, we measured the expression levels of Nupr1, ER stress protein markers CHOP and Trib3, apoptosis-related protein markers cleaved-caspase3 and PARP, as well as autophagy-related protein markers LC3 and Beclin-1 in brain tissues of adult male Sprague-Dawley (SD) rats, rat primary cultured neurons and the rat adrenal pheochromocytoma cells (PC12 cells) after METH exposure. We also determined the effects of METH exposure on the expression of these proteins after silencing Nupr1, CHOP, or Trib3 expression with synthetic small hairpin RNA (shRNA) or siRNA in vitro, and after silencing Nupr1 in the striatum of rats by injecting lentivirus containing shRNA sequence targeting Nupr1 gene to rat striatum. The results showed that METH exposure increased Nupr1 expression that was accompanied with increased expression of ER stress protein markers CHOP and Trib3, and also led to apoptosis and autophagy in rat primary neurons and in PC12 cells after 24 h exposure (3.0 mM), and in the prefrontal cortex and striatum of rats after repeated intraperitoneal injections (15 mg/kg × 8 injections at 12 h intervals). Silencing of Nupr1 expression partly reduced METH-induced apoptosis and autophagy in vitro and in vivo. These results suggest that Nupr1 plays an essential role in METH-caused neuronal apoptosis and autophagy at relatively higher doses and may be a potential therapeutic target in high-dose METH-induced neurotoxicity.

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Section: Resultsmentioning

confidence: 99%

“…The synthesis of shRNA and stereotaxic injection protocol were based on our recent studies (Huang et al, 2015; Chen R. et al, 2016; Li et al, 2017). In brief, the Nupr1 shRNA #2 sequence (TCCTGGATGAGTATGACCA) was cloned into pGC-LV vector and transfected into HEK293FT cells with pHelper 1.0 and 2.0 vectors.…”

Section: Methodsmentioning

confidence: 99%

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Huang

Tai

et al. 2017

Front. Mol. Neurosci.

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“…Neuronal culture neurons were maintained for up to 5–7 days and then used for subsequent experiments. Primary cultures of prefrontal cortical and striatal neurons were exposed to 0.2 mM, 0.4 mM, 0.6 mM, 0.8 mM and 1.0 mM METH for 24 h. These concentrations were based on the LC25 (0.58 mM) of METH in primary cultured neurons as measured in our lab (Chen R. et al, 2016; Xu et al, 2017). Furthermore, these concentrations are semblable between used in the SH-SY5Y cells and primary cultured neurons.…”

Section: Methodsmentioning

confidence: 99%

“…The synthesis of the lentiviruses was based on our recent studies (Qiao et al, 2014; Chen R. et al, 2016). In brief, the sequences of WT α-syn, and α-syn-2KR (K96R and K102R) were cloned into a pGag/Pol-LV vector and transfected into HEK293FT cells with pRev 1.0 and pVSV-G vectors.…”

Section: Methodsmentioning

confidence: 99%

“…AAV2-EGFP was used as the control. The stereotaxic injection protocol was based on the studies from our lab (Chen R. et al, 2016; Xu et al, 2017). Healthy adult male C57 mice were divided randomly into five groups ( n = 5/group): the AAV2-EGFP group, the AAV2-WT α-syn group, the AAV2-α-syn-2KR group, the AAV2-WT α-syn + METH group, and the AAV2-α-syn-2KR + METH group.…”

Section: Methodsmentioning

confidence: 99%

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SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

Zhu

Qiao

Chen

et al. 2018

Front. Cell. Neurosci.

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Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson’s disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (α-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of α-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of α-syn is involved in high-dose METH-induced α-syn aggregation. We measured the levels of α-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of α-syn SUMOylation on α-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of α-syn by transfecting a lentivirus containing the sequence of WT α-syn or K96/102R α-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT α-syn or K96/102R α-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of α-syn, although the expression of α-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in α-syn SUMOylation by UBC9 overexpression relieves METH-induced α-syn overexpression and aggregation, whereas the decrease in α-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of α-syn also aggravate α-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of α-syn plays a fundamental part in α-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.

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Cardiotoxicity of Drugs

Varga

Pacher

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes

Cited by 50 publications

References 41 publications

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

Cardiotoxicity of Drugs

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