Apelin-13 protects dopaminergic neurons in MPTP-induced Parkinson’s disease model mice through inhibiting endoplasmic reticulum stress and promoting autophagy

Zhu, Jingxian; Dou, Shanshan; Jiang, Yunlu; Chen, Jing; Wang, Chunmei; Cheng, Baohua

doi:10.1016/j.brainres.2019.03.027

Cited by 44 publications

(30 citation statements)

References 33 publications

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“…The pan-injury-DOWN signature included genes involved in lipid metabolism (Acss2, Bbox1, Elovl2, Fzd2, Hmgcs1, Sqle), and other relevant genes such as Apln, Insig1, Ppargc1a, and Ttpa. Apln encodes for apelin, a secreted peptide that has been shown to be neuroprotective in multiple acute injury and chronic neurodegenerative models [111][112][113][114][115]. Insig1 encodes for insulin induced gene 1 and its downregulation suggests a globally reduced insulin signaling [116].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

Das

Noori

et al. 2020

J Neuroinflammation

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Background: Neuronal damage in acute CNS injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction in both mice and humans. However, whether and how the nature of the CNS insult-acute versus chronic-influences the astrocyte response, and whether astrocyte transcriptomic changes in these mouse models faithfully recapitulate the astrocyte reaction in human diseases remains to be elucidated. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, besides a shared "pan-injury" signature common to both types of conditions, and investigated the presence of these mouse astrocyte signatures in transcriptomic studies from human neurodegenerative diseases. Methods: We performed a meta-analysis of 15 published astrocyte transcriptomic datasets from mouse models of acute injury (n = 6) and chronic neurodegeneration (n = 9) and identified pan-injury, acute, and chronic signatures, with both upregulated (UP) and downregulated (DOWN) genes. Next, we investigated these signatures in 7 transcriptomic datasets from various human neurodegenerative diseases. Results: In mouse models, the number of UP/DOWN genes per signature was 64/21 for pan-injury and 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan-injury-UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (Gfap and Vim), plus extracellular matrix (i.e., Cd44, Lgals1, Lgals3, Timp1), and immune response (i.e., C3, Serping1, Fas, Stat1, Stat2, Stat3). The acute injury-UP signature was enriched in protein synthesis and degradation (both ubiquitin-proteasome and autophagy systems), intracellular trafficking, and anti-oxidant defense genes, whereas the acute injury-DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which are transcriptional repressors. The chronic neurodegeneration-UP signature was further enriched in astrocyte-secreted extracellular matrix proteins (Lama4, Cyr61, Thbs4), while the DOWN signature included relevant genes such as Agl (glycogenolysis), S1pr1 (immune modulation), and Sod2 (anti-oxidant). Only the pan-injury-UP mouse signature was clearly present in some human

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Section: Discussionmentioning

confidence: 99%

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

Das

Noori

et al. 2020

J Neuroinflammation

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“…Apelin expression has been described in endothelial cells and the CNS [82] and has also been found to be involved in neuronal dysfunction related to inflammation during ageing [83]. Modulation of apelin signalling has been discussed in a range of pathologies [84] and has recently also been associated with neurodegenerative diseases [85], including AD [86][87][88][89] and PD [90][91][92]. However, specific roles in PD remain to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

“…However, specific roles in PD remain to be further investigated. Apelin signalling has been linked to autophagy in PD, both in cellular in vitro and in vivo mouse models [90,92]. PD mouse models have shown roles for apelin in MPTP-induced damage affecting the substantia nigra, behavioral dysfunction and dopaminergic neurodegeneration [90].…”

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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“…More recently, long noncoding RNA HAGLROS modulated autophagy and apoptosis by controlling PI3K/Akt/mTOR activation and miR-100/ATG10 signaling in PD [56]. In the brain, apelin-13 protected dopaminergic neurons in MPTP-induced PD model mice in vivo, through inhibiting ERS and promoting autophagy [17]. However, there has been a controversial report that apelin-13 relieves traumatic brain damage-produced injury through repressing autophagy [57].…”

Section: Discussionmentioning

confidence: 99%

Apelin-13 Protects Dopaminergic Neurons against Rotenone—Induced Neurotoxicity through the AMPK/mTOR/ULK-1 Mediated Autophagy Activation

Chen

Wang

Chen

et al. 2020

IJMS

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Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Several brain–gut peptides are able to exert neuroprotective effects on the nigrostriatal dopaminergic system. Apelin-13 is a neuropeptide, conveying potential neuroprotective activities. However, whether, and how, apelin-13 could antagonize rotenone-induced neurotoxicity has not yet been elucidated. In the present study, rotenone-treated SH-SY5Y cells and rats were used to clarify whether apelin-13 has protective effects on dopaminergic neurons, both in vivo and in vitro. The results showed that apelin-13 could protect SH-SY5Y cells from rotenone-induced injury and apoptosis. Apelin-13 was able to activate autophagy, and restore rotenone induced autophagy impairment in SH-SY5Y cells, which could be blocked by the autophagy inhibitor 3-Methyladenine. Apelin-13 activated AMPK/mTOR/ULK-1 signaling, AMPKα inhibitor compound C, as well as apelin receptor blockage via siRNA, which could block apelin-13-induced signaling activation, autophagy activation, and protective effects, in rotenone-treated SH-SY5Y cells. These results indicated that apelin-13 exerted neuroprotective properties against rotenone by stimulating AMPK/mTOR/ULK-1 signaling-mediated autophagy via the apelin receptor. We also observed that intracerebroventricular injection of apelin-13 could alleviate nigrostriatal dopaminergic neuron degeneration in rotenone-treated rats. Our findings provide new insights into the mechanism by which apelin-13 might attenuate neurotoxicity in PD.

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Apelin-13 protects dopaminergic neurons in MPTP-induced Parkinson’s disease model mice through inhibiting endoplasmic reticulum stress and promoting autophagy

Cited by 44 publications

References 33 publications

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

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

Apelin-13 Protects Dopaminergic Neurons against Rotenone—Induced Neurotoxicity through the AMPK/mTOR/ULK-1 Mediated Autophagy Activation

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