lncRNA NEAT1 prompts autophagy and apoptosis in MPTP-induced Parkinson’s disease by impairing miR-374c-5p

Abstract Long non-coding RNAs (lncRNAs) play biological roles in brain disorder and neurodegenerative diseases. As the functions of lncRNA NEAT1 in Parkinson’s disease (PD) remain unknown, in the present study, we aimed to explore the roles and underlying molecular mechanisms of NEAT1 in PD. A PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and a cell model of SH-SY5Y induced by N-methyl-4-phenylpyridinium (MPP+) were established. The ratio of tyrosine hydroxylase (TH+) cells was determined by immunofluorescence assay, and the behavioral changes in mice were observed using pole tests and rotarod tests. The cellular viability and apoptosis of SH-SY5Y were detected by MTT assay and flow cytometric analysis, respectively, and the number of autophagosomes was subsequently measured by transmission electron microscopy. High-performance liquid chromatography was performed to detect the content of dopamine, and a dual-luciferase reporter assay was used to clarify the target of NEAT1 simultaneously. The results demonstrated that the level of NEAT1 was upregulated in the MPTP-induced PD mice, dopamine neurons, and the SH-SY5Y cells treated with MPP+, whereas the level of miR-374c-5p was downregulated. NEAT1 level was positively correlated with MPP+ in a concentration-dependent manner. NEAT1 inhibition efficiently facilitated cell proliferation but inhibited apoptosis and autophagy in the MPP+-treated SH-SY5Y cells. Additionally, silencing of NEAT1 increased the TH+ rate of neurons and suppressed autophagy greatly in PD mice. As a possible target of NEAT1, miR-374c-5p could impact on the apoptosis and autophagy of the SH-SY5Y cells. NEAT1 inhibition upregulated the expression of miR-374c-5p, enhanced SH-SY5Y cell viability, and repressed autophagy and apoptosis in MPTP-induced PD mice. These findings indicated a potential therapeutic role of NEAT1 in treating PD.

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Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.626128 ◽

2021 ◽

Vol 15 ◽

Author(s):

Nolwazi Z. Gcwensa ◽

Drèson L. Russell ◽

Rita M. Cowell ◽

Laura A. Volpicelli-Daley

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Disease Onset ◽

Neuronal Cell ◽

Rem Sleep Behavior Disorder ◽

Dopamine Neurons ◽

Neuronal Cell Body ◽

Substantia Nigra Pars Compacta ◽

Cognitive Changes

Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

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Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

Science ◽

10.1126/science.aat8407 ◽

2018 ◽

Vol 362 (6414) ◽

pp. eaat8407 ◽

Cited By ~ 104

Author(s):

Tae-In Kam ◽

Xiaobo Mao ◽

Hyejin Park ◽

Shih-Ching Chou ◽

Senthilkumar S. Karuppagounder ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Parp Inhibitors ◽

Dopamine Neurons ◽

Parp Activation ◽

Disease Modifying Therapy ◽

Genetic Deletion ◽

Disease Modifying ◽

Parp 1

The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson’s disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.

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Fractionally delineate the neuroprotective function of calbindin-D28k in Parkinson’s disease

International Journal of Biomathematics ◽

10.1142/s1793524518501036 ◽

2018 ◽

Vol 11 (08) ◽

pp. 1850103 ◽

Cited By ~ 5

Author(s):

Hardik Joshi ◽

Brajesh Kumar Jha

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dimensional Space ◽

Cytosolic Calcium ◽

The Body ◽

Dopamine Neurons ◽

Reaction Diffusion Equation ◽

Substantia Nigra Pars Compacta ◽

Brain Disorder ◽

The Brain

Neuron is a fundamental unit of the brain, which is specialized to transmit information throughout the body through electrical and chemical signals. Calcium ([Formula: see text]) ions are known as second messengers which play important roles in the movement of the neurotransmitter. Calbindin-[Formula: see text] is a [Formula: see text] binding protein which is involved in regulation of intracellular [Formula: see text] ions and maintains [Formula: see text] homeostasis level, it also alters the cytosolic calcium concentration ([[Formula: see text]]) in nerve cells to keep the cell alive. Parkinson’s disease (PD) is a chronic progressive neurodegenerative brain disorder of the nervous system. Several regions of the brain indicate the hallmark of the PD. The symptoms of PD are plainly linked with the degeneration and death of dopamine neurons in the substantia nigra pars compacta located in midbrain which is accompanied by depletion in calbindin-[Formula: see text]. In the present paper, the neuroprotective role of calbindin-[Formula: see text] in the cytoplasmic [[Formula: see text]] distribution is studied. The elicitation in [[Formula: see text]] is due to the presence of low amount of calbindin-[Formula: see text] which can be portrayed and is a hallmark of PD. A one-dimensional space time fractional reaction diffusion equation is designed by keeping in mind the physiological condition taking place inside Parkinson’s brain. Computational results are performed in MATLAB.

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MicroRNA-409-3p Targeting at ATXN3 Reduces the Apoptosis of Dopamine Neurons Based on the Profile of miRNAs in the Cerebrospinal Fluid of Early Parkinson’s Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.755254 ◽

2022 ◽

Vol 9 ◽

Author(s):

Xuling Tan ◽

Junjian Hu ◽

Fengyu Ming ◽

Lingling Lv ◽

Weiqian Yan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

Dopamine Neurons ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Real Time Quantitative Pcr ◽

Gene Assay ◽

Next Generation Sequencing Ngs ◽

Early Parkinson’S Disease

Precise recognition of early Parkinson’s disease (PD) has always been a challenging task requiring more feasible biomarkers to be integrated to improve diagnostic accuracy. MicroRNAs (miRNAs) of cerebrospinal fluid (CSF) are believed to be potential and promising candidate biomarkers for PD. However, the role of altered miRNAs of CSF play in PD is unclear. Here, we recruited patients with early stages of PD and controls to analyze the expression of miRNA in CSF by the Next Generation Sequencing (NGS). Furthermore, we tested the levels of these miRNA in SH-SY5Y cells treated with MPP+ using real-time quantitative PCR. We found 21 miRNAs were upregulated in CSF of early PD patients and miR-409-3p, one of the identified 21 miRNAs, was further confirmed in SH-SY5Y cells treated with MPP+. Also, more cells survived in the overexpression of the miR-409-3p group when SH-SY5Y cells and mice were treated with MPP+ and MPTP, respectively. Mechanistically, we demonstrated the binding of miR-409-3p and 3’UTR of ATXN3 through a dual luciferase reporter gene assay. Moreover, miR-409-3p mimic reduced the aggregation of polyglutamine-expanded mutant of ATXN3 and apoptosis. Our results provide experimental evidence for miR-409-3p in CSF as a diagnostic marker of PD.

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Effect of Vasicinone against Paraquat-Induced MAPK/p53-Mediated Apoptosis via the IGF-1R/PI3K/AKT Pathway in a Parkinson’s Disease-Associated SH-SY5Y Cell Model

Nutrients ◽

10.3390/nu11071655 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1655 ◽

Cited By ~ 5

Author(s):

Da-Tong Ju ◽

Kalaiselvi Sivalingam ◽

Wei-Wen Kuo ◽

Tsung-Jung Ho ◽

Ruey-Lin Chang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Model ◽

Neuroprotective Effect ◽

Mitogen Activated Protein Kinase ◽

Potential Candidate ◽

Dependent Manner ◽

Mitogen Activated Protein ◽

Cellular Apoptosis ◽

Apoptotic Pathways

Vasicinone is a quinazoline alkaloid isolated from the Adhatoda vasica plant. In this study, we explored the neuroprotective effect and underlying molecular mechanism of vasicinone against paraquat-induced cellular apoptosis in SH-SY5Y cells. Vasicinone reduced the paraquat-induced loss of cell viability, rescued terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic nuclei, and suppressed generation of reactive oxygen species (ROS) in a dose-dependent manner. Western blotting analysis revealed that vasicinone increased the phosphorylation of IGF1R/PI3K/AKT cell survival signaling molecules and downregulated the paraquat-induced, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)-mediated apoptotic pathways compared to that observed in cells not treated with vasicinone. This protection depended critically on the activation of IGF1R, and the silencing of IGF1R by siRNA completely abrogated the protective effect of vasicinone in SH-SY5Y cells. Our findings indicated that vasicinone is a potential candidate for the treatment of Parkinson’s disease and possibly other oxidative stress-related neurodegenerative disorders.

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LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson’s disease through RAB3IP

Biological Chemistry ◽

10.1515/hsz-2018-0431 ◽

2019 ◽

Vol 400 (9) ◽

pp. 1217-1228 ◽

Cited By ~ 21

Author(s):

Qiuyu Lin ◽

Sen Hou ◽

Yuyin Dai ◽

Nan Jiang ◽

Yingjie Lin

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Noncoding Rna ◽

Rna Binding ◽

Quantitative Polymerase Chain Reaction ◽

Flow Cytometric Analysis ◽

Luciferase Assay ◽

Dependent Manner ◽

Competing Endogenous Rnas

Abstract Parkinson’s disease (PD) is a common neurological disorder characterized by dopaminergic (DA) neuron degeneration and death in the midbrain, and the long noncoding RNA HOTAIR has been shown to affect disease progression in PD. In this study, we aimed to further illustrate the molecular mechanism of HOTAIR in PD. Bioinformatics analysis was utilized to determine the potential downstream targets of HOTAIR in PD. Luciferase assay and the RNA Binding Protein Immunoprecipitation (RIP) assay were used to validate the existence of binding sites between competing endogenous RNAs (ceRNAs). Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting indicated that HOTAIR and RAB3IP increased while miR-126-5p decreased in PD cells and PD mice. Additionally, the CCK-8 assay and flow cytometric analysis indicated that the knockdown of HOTAIR and RAB3IP and the overexpression of miR-126-5p significantly increased cell proliferation and reduced apoptosis in PD cells. Furthermore, the results of in vivo experiments suggested that knockdown of HOTAIR expression increased the number of TH-positive cells and the number of α-synuclein-positive cells decreased while reducing the apoptosis rate among DA neurons. Our study confirmed that HOTAIR promotes PD progression by regulating miR-126-5p and RAB3IP in a ceRNA-dependent manner and further clarified how HOTAIR works in PD.

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LncRNA SOX2-OT Participates in Parkinson’s Disease Through Regulating miRNA-942-5p/NAIF1 Axis

10.21203/rs.3.rs-763972/v1 ◽

2021 ◽

Author(s):

Yabi Guo ◽

Yanyang Liu ◽

Hong Wang ◽

Peijun Liu

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Apoptosis ◽

Cell Model ◽

Luciferase Reporter ◽

Sod Activity ◽

Software Analysis ◽

Direct Target

Abstract Parkinson’s disease (PD) is a neurodegenerative disease. Studies have shown that lncRNA SOX2-OT was highly expressed in PD patients, but its specific functions and mechanisms still need further research. This study aimed to explore whether lncRNA SOX2-OT could regulate oxidative stress, inflammation and neuronal apoptosis in PD in vitro model and explored the underlying mechanism. An in vitro PD cell model was induced by 1-methyl-4-phenylpyridinium (MPP+). The results of the biological software analysis and luciferase reporter assay indicated that miR-942-5p was a direct target of lncRNA SOX2-OT, and NAIF1 was a direct target of miR-942-5p. Experiments showed that the expression levels of lncRNA SOX2-OT and NAIF1 were increased, and miR-942-5p expression was decreased in SH-SY5Y cells following MPP+ treatment. In addition, MPP+ treatment reduced SH-SY5Y cell viability, induced apoptosis, increased cleaved-Caspase3 protein expression, and increased cleaved-Caspase3/Caspase3 ratio, increased LDH viability, and increased the levels of TNF-α, IL-1β and ROS in SH-SY5Y cells, reduced SOD activity, however, all these effects were inhibited by SOX2-OT-siRNA, and these inhibitions were reversed by miR-942-5p inhibitor. Moreover, the protective role of miR-942-5p mimic in MPP+ induced SH-SY5Y cells was significantly eliminated by NAIF1-plasmid. In summary, this study confirmed that lncRNA SOX2-OT regulated oxidative stress, inflammation and neuronal apoptosis via directly regulating the miR-942-5p/NAIF1 signal axis, and then participated in the occurrence and development of PD. These data provide a new potential targets for PD diagnosis and treatment.

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Current Approaches and Molecular Mechanisms for Directly Reprogramming Fibroblasts Into Neurons and Dopamine Neurons

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.738529 ◽

2021 ◽

Vol 13 ◽

Author(s):

Fabin Han ◽

Yanming Liu ◽

Jin Huang ◽

Xiaoping Zhang ◽

Chuanfei Wei

Keyword(s):

Parkinson’S Disease ◽

Stem Cells ◽

Parkinson's Disease ◽

Immune System ◽

Neural Stem Cells ◽

Molecular Mechanisms ◽

Embryonic Stem ◽

Dopamine Neurons ◽

Patient Specific ◽

Direct Reprogramming

Parkinson’s disease is mainly caused by specific degeneration of dopaminergic neurons (DA neurons) in the substantia nigra of the middle brain. Over the past two decades, transplantation of neural stem cells (NSCs) from fetal brain-derived neural stem cells (fNSCs), human embryonic stem cells (hESCs), and induced pluripotent stem cells (iPSCs) has been shown to improve the symptoms of motor dysfunction in Parkinson’s disease (PD) animal models and PD patients significantly. However, there are ethical concerns with fNSCs and hESCs and there is an issue of rejection by the immune system, and the iPSCs may involve tumorigenicity caused by the integration of the transgenes. Recent studies have shown that somatic fibroblasts can be directly reprogrammed to NSCs, neurons, and specific dopamine neurons. Directly induced neurons (iN) or induced DA neurons (iDANs) from somatic fibroblasts have several advantages over iPSC cells. The neurons produced by direct transdifferentiation do not pass through a pluripotent state. Therefore, direct reprogramming can generate patient-specific cells, and it can overcome the safety problems of rejection by the immune system and teratoma formation related to hESCs and iPSCs. However, there are some critical issues such as the low efficiency of direct reprogramming, biological functions, and risks from the directly converted neurons, which hinder their clinical applications. Here, the recent progress in methods, mechanisms, and future challenges of directly reprogramming somatic fibroblasts into neurons or dopamine neurons were summarized to speed up the clinical translation of these directly converted neural cells to treat PD and other neurodegenerative diseases.

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Transgenic Mice Expressing Human α-Synuclein 1-103 Fragment as a Novel Model of Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.760781 ◽

2021 ◽

Vol 13 ◽

Author(s):

Ye Tian ◽

Mingyang He ◽

Lina Pan ◽

Xin Yuan ◽

Min Xiong ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Sequencing Analysis ◽

Dependent Manner ◽

Mouse Line ◽

Transgenic Mouse Line ◽

Age Dependent ◽

The Central Nervous System ◽

Behavioral Impairments

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. However, its cellular and molecular mechanisms still wrap in the mist. This is partially caused by the absence of appropriate animal models mimicking sporadic PD that constitutes the majority of cases. Previously, we reported that a cysteine protease, asparagine endopeptidase (AEP), is activated in an age-dependent manner, and cleaves α-synuclein in the brain of sporadic PD patients. The AEP-derived α-synuclein 1-103 fragment is required for the pathogenesis of PD. Thus, we designed and characterized a novel transgenic mouse line expressing α-synuclein 1-103 (designated N103 mice). This model shows an abundant accumulation of pathological α-synuclein in the central nervous system, loss of dopaminergic neurons in the substantia nigra, and progressive striatal synaptic degeneration. The N103 mice also manifest age-dependent PD-like behavioral impairments. Notably, the mice show weight loss and constipation, which are the common non-motor symptoms in PD. The RNA-sequencing analysis found that the transcriptomics pattern was extensively altered in N103 mice. In conclusion, the N103 mouse line, as a brand-new tool, might provide new insights into PD research.

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MiR-30a-5p regulates GLT-1 function via a PKCα-mediated ubiquitin degradation pathway in a mouse model of Parkinson’s disease

10.21203/rs.2.24022/v1 ◽

2020 ◽

Author(s):

Xingjun Meng ◽

Jianping Zhong ◽

Chong Zeng ◽

Ken Kin Lam Yung ◽

Xiuping Zhang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Cell Model ◽

Glutamate Transporters ◽

Acid Uptake ◽

Dependent Manner ◽

The Impact

Abstract Background:Glutamate excitotoxicity caused by dysfunctional glutamate transporters plays an important role in the pathogenesis of Parkinson’s disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not fully elucidated. MicroRNAs have been reported to play key roles in regulating the translation of glutamate-transporter mRNA. Methods: We established model of PD 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice in vivo and 1-methyl-4-phenylpyridinium (MPP+) treated astrocyte in vitro. Stereotaxic injection of shRNA in mouse, and miRNA inhibitor/mimic, or antagonist/agonist treated the cell model, Behavioral experiments, glutamic acid uptake, transport activity of synaptosomes, underlying mechanisms and the impact on neuronal survival were assessed.Results We demonstrated that short-hairpin RNA-mediated knockdown of miR-30a-5p ameliorated motor deficits and pathological changes like astrogliosis and reactive microgliosis in a mouse model of PD. Western blotting and immunofluorescent labeling revealed that miR-30a-5p suppressed the expression and function of GLT-1 in MPTP-treated mice and specifically in astrocytes treated with (cell model of PD). Conclusion Both in vitro and in vivo, we found that miR-30a-5p knockdown promoted glutamate uptake and increased GLT-1 expression by hindering GLT-1 ubiquitination and subsequent degradation in a PKCα-dependent manner. Therefore, miR-30a-5p represents a potential therapeutic target for the treatment of PD.

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