Neuropeptides, excitatory amino acid and adenosine A2 receptors regulate D2 receptors via intramembrane receptor-receptor interactions. Relevance for Parkinson's disease and schizophrenia

Background/Aims: Parkinson’s disease (PD) is a frequently occurring condition that resulted from the loss of midbrain neurons, which synthesize the neurotransmitter dopamine. In this study, we established mouse models of PD to investigate the expression of microRNA-128 (miR-128) and mechanism through which it affects apoptosis of dopamine (DA) neurons and the expression of excitatory amino acid transporter 4 (EAAT4) via binding to axis inhibition protein 1 (AXIN1). Methods: Gene expression microarray analysis was performed to screen differentially expressed miRNAs that are associated with PD. The targeting relationship between miR-128 and AXIN1 was verified via a bioinformatics prediction and dual-luciferase reporter gene assay. After separation, DA neurons were subjected to a series of inhibitors, activators and shRNAs to validate the mechanisms of miR-128 in controlling of AXIN1 in PD. Positive protein expression of AXIN1 and EAAT4 in DA neurons was determined using immunocytochemistry. miR-128 expression and the mRNA and protein levels of AXIN1 and EAAT4 were evaluated via RT-qPCR and Western blot analysis, respectively. DA neuron apoptosis was evaluated using TUNEL staining. Results: We identified AXIN1 as an upregulated gene in PD based on the microarray data of GSE7621. AXIN1 was targeted and negatively mediated by miR-128. In the DA neurons, upregulated miR-128 expression or sh-AXIN1 increased the positive expression rate of EAAT4 together with mRNA and protein levels, but decreased the mRNA and protein levels of AXIN1, apoptosis rate along with the positive expression rate of AXIN1; however, the opposite trend was found in response to transfection with miR-128 inhibitors. Conclusion: Evidence from experimental models revealed that miR-128 might reduce apoptosis of DA neurons while increasing the expression of EAAT4 which might be related to the downregulation of AXIN1. Thus, miR-128 may serve as a potential target for the treatment of PD.

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Neurotensin NTS1-Dopamine D2 Receptor-Receptor Interactions in Putative Receptor Heteromers: Relevance for Parkinson’s Disease and Schizophrenia

Current Protein and Peptide Science ◽

10.2174/1389203715666140901105253 ◽

2014 ◽

Vol 15 (7) ◽

pp. 681-690 ◽

Cited By ~ 14

Author(s):

Luca Ferraro ◽

Sarah Beggiato ◽

Dasiel Borroto-Escuela ◽

Laura Ravani ◽

William O'Connor ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Dopamine D2 ◽

Putative Receptor ◽

Receptor Heteromers ◽

Receptor Interactions

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Recent Advance in the Relationship between Excitatory Amino Acid Transporters and Parkinson’s Disease

Neural Plasticity ◽

10.1155/2016/8941327 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Yunlong Zhang ◽

Feng Tan ◽

Pingyi Xu ◽

Shaogang Qu

Keyword(s):

Parkinson’S Disease ◽

Amino Acid ◽

Animal Models ◽

Substantia Nigra ◽

Excitatory Amino Acid ◽

Synaptic Cleft ◽

Dopamine Neurons ◽

Amino Acid Transporters ◽

Excitatory Amino Acid Transporters ◽

And Function

Parkinson’s disease (PD) is the most common movement disorder disease in the elderly and is characterized by degeneration of dopamine neurons and formation of Lewy bodies. Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). If glutamate is not removed promptly in the synaptic cleft, it will excessively stimulate the glutamate receptors and induce excitotoxic effects on the CNS. With lack of extracellular enzyme to decompose glutamate, glutamate uptake in the synaptic cleft is mainly achieved by the excitatory amino acid transporters (EAATs, also known as high-affinity glutamate transporters). Current studies have confirmed that decreased expression and function of EAATs appear in PD animal models. Moreover, single unilateral administration of EAATs inhibitor in the substantia nigra mimics several PD features and this is a solid evidence supporting that decreased EAATs contribute to the process of PD. Drugs or treatments promoting the expression and function of EAATs are shown to attenuate dopamine neurons death in the substantia nigra and striatum, ameliorate the behavior disorder, and improve cognitive abilities in PD animal models. EAATs are potential effective drug targets in treatment of PD and thus study of relationship between EAATs and PD has predominant medical significance currently.

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Loss of response to levodopa in Parkinson’s disease and co-occurrence with dementia: role of D3 and not D2 receptors

Brain Research ◽

10.1016/s0006-8993(02)03396-6 ◽

2002 ◽

Vol 955 (1-2) ◽

pp. 138-152 ◽

Cited By ~ 49

Author(s):

J.N Joyce ◽

H.L Ryoo ◽

T.B Beach ◽

J.N Caviness ◽

Mark Stacy ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

D2 Receptors ◽

Loss Of Response

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Blood Exosomes Have Neuroprotective Effects in a Mouse Model of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3807476 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Ting Sun ◽

Zhe-Xu Ding ◽

Xin Luo ◽

Qing-Shan Liu ◽

Yong Cheng

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Amino Acid ◽

Dopaminergic Neurons ◽

Motor Coordination ◽

Oxidized Lipids ◽

Metabolomic Analysis ◽

Neuroprotective Effects ◽

And Control

Parkinson’s disease (PD) is a common and complex neurodegenerative disease; the pathogenesis of which is still uncertain. Exosomes, nanosized extracellular vesicles, have been suggested to participate in the pathogenesis of PD, but their role is unknown. Here, a metabolomic analysis of serum and brain exosomes showed differentially expressed metabolites between 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride- (MPTP-) induced PD mice and control mice, such as oxidized lipids, vitamins, and cholesterol. These metabolites were enriched in coenzyme, nicotinamide, and amino acid pathways related to PD, and they could be served as preclinical biomarkers. We further found that blood-derived exosomes from healthy volunteers alleviated impaired motor coordination in MPTP-treated mice. Results from immunohistochemistry and western blotting indicated that the loss of dopaminergic neurons in substantia nigra and striatum of PD model mice was rescued by the exosome treatment. The exosome treatment also restored the homeostasis of oxidative stress, neuroinflammation, and cell apoptosis in the model mice. These results suggest that exosomes are important mediators for PD pathogenesis, and exosomes are promising targets for the diagnosis and treatment of PD.

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