Apelin-36 mediates neuroprotective effects by regulating oxidative stress, autophagy and apoptosis in MPTP-induced Parkinson’s disease model mice

Zhu, Jingxian; Gao, Wenbin; Shan, Xuehua; Wang, Chunmei; Wang, Huiqing; Shao, Ziqi; Dou, Shanshan; Jiang, Yunlu; Wang, Chuangong; Cheng, Baohua

doi:10.1016/j.brainres.2019.146493

Cited by 54 publications

(29 citation statements)

References 65 publications

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“…PD mouse models have shown roles for apelin in MPTP-induced damage affecting the substantia nigra, behavioral dysfunction and dopaminergic neurodegeneration [90]. Roles for apelin signalling in endoplasmic reticulum (ER) stress have also been identified [91] and neuroprotective roles of apelin signalling pathways have recently been identified in PD mouse models [93]. The current study is the first to identify apelin signalling pathways to be associated with protein deimination, and such post-translational regulation of apelin via deimination, as identified here in pre-motor PD model plasma-EVs, may play important roles in the multifaceted roles of apelin signalling.…”

Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to "Alzheimer's disease", "PD", "Huntington's disease", "prion diseases", as well as for "oxidative phosphorylation", "thermogenesis", "metabolic pathways", "Staphylococcus aureus infection", gap junction, "platelet activation", "apelin signalling", "retrograde endocannabinoid signalling", "systemic lupus erythematosus", and "non-alcoholic fatty liver disease". Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD. Figure 2. EV characterisation from rat plasma. (A) Representative Nanosight graphs showing nanoparticle tracking analysis (NTA) analysis of plasma EV profiles from sham-treated rats (Sham; n = 3). (B) Representative Nanosight graphs showing NTA analysis of plasma EV profiles from the premotor PD rat models (PD; n = 3). (C) Western blotting (WB) confirms that rat plasma-EVs are positive for the EV-specific markers CD63 and flotillin-1 (Flot-1); the molecular weight standard is indicated in kilo Daltons (kDa). (D,E) Transmission electron microscopy (TEM) images showing EVs isolated from sham (D) and pre-motor PD model (PD; (E)) rat plasma, revea...

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Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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“…Apelin was found to attenuate early brain injury via suppressing neuronal apoptosis through the PI3K/Akt signaling [23]. Apelin mediated neuroprotective effects by regulating oxidative stress, autophagy and apoptosis [24], as well as alleviated neuroinflammation [25]. It was possible that the neuroprotective effects of MTHFD2-associated apelin signaling pathway may play a vital role in LGG development.…”

Section: Discussionmentioning

confidence: 99%

Up-regulated Expression of MTHFD2 Correlates with Favorable Prognosis in LGG Patients: A Bioinformatic Analysis

Shi¹,

Zhang²,

Shou³

et al. 2020

Preprint

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Background Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was found to be up-regulated in various cancers and has been identified as a potential target for cancer treatment, but the potential function of MTHFD2 in low-grade gliomas (LGG) has not been well-examined. This study initially revealed the potential function of MTHD2 and emphasized its importance in LGG. Methods We first explored the expression of MTHFD2 in LGG patients using Oncomine and UALCAN database. Survival analysis on LGG patients was then conducted based on age, gender, radiation therapy, histologic grade, tumor type and MTHFD2 expression. Cox regression analysis was also applied to predict the prognostic factor for overall survival (OS) of LGG. Finally, we performed enrichment analysis to reveal the potential MTHFD2-associated pathways involved in LGG. Results We found that MTHFD2 is highly expressed in LGG patients, and MTHFD2 expression is related with age, sub-types and TP53-mutation status (all P<0.05). Age, radiation therapy, histologic grade and tumor type were implicated in the survival of LGG patients (all P<0.05). High expression of MTHFD2 desirably improved the prognosis of LGG patients (P<0.001), especially for those patients with characteristics of age≥45 years old (P<0.001), receiving radiation therapy treatment (P=0.001), sub-type of astrocytoma and oligodendroglioma (all P<0.05), and histologic grade 3 (P<0.05). MTHFD2 was determined as an independent prognostic factor with age and grade for OS of LGG patients (all P<0.01). Pathway enrichment analysis indicated that MTHFD2 mainly participates in mTOR signaling pathway, apelin pathway and folate-mediated one-carbon metabolism.Conclusions The expression of MTHFD2 is associated with key clinical phenotype. High expression of MTHFD2 is favorable for the overall survival of LGG patients. MTHFD2 may serve as a novel prognostic biomarker and potential therapeutic target for LGG treatment.

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“…Furthermore, in MPTP-induced PD mice, they demonstrated that the neuroprotection induced by Apelin-36 could be explained by its effect on the reduction of oxidative stress and nitrated α-syn expression. Apelin-36 also promoted autophagy and inhibited ASK1/JNK/caspase-3 apoptotic pathway [422]. Finally, the activation of the transcription factor Nrf2/antioxidant response element (ARE) pathway has shown to protect against neurodegeneration by decreasing both oxidative stress and protein aggregation [423].…”

Section: Other Antioxidant Strategiesmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Apelin-36 mediates neuroprotective effects by regulating oxidative stress, autophagy and apoptosis in MPTP-induced Parkinson’s disease model mice

Cited by 54 publications

References 65 publications

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Up-regulated Expression of MTHFD2 Correlates with Favorable Prognosis in LGG Patients: A Bioinformatic Analysis

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

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