Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson’s Disease in a Mouse Model

Parkinson’s disease (PD) is the second most common neurodegenerative disease and although many studies have been done on this disease, the underlying mechanisms are still poorly understood and further studies are warranted. Therefore, this study identified circRNA expression profiles in the cerebral cortex (CC), hippocampus (HP), striatum (ST), and cerebellum (CB) regions of the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model using RNA sequencing (RNA-seq), and differentially expressed circRNA were validated using reverse transcription quantitative real-time PCR (qRT-PCR). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analyses were also performed to explore the potential function of circRNAs. The results show that, compared with the control group, 24, 66, 71, and 121 differentially expressed circRNAs (DE-circRNAs) were found in the CC, HP, ST, and CB, respectively. PDST vs. PDCB, PDST vs. PDHP, and PDCB vs. PDHP groups have 578, 110, and 749 DE-circRNAs, respectively. Then, seven DE-cirRNAs were selected for qRT-PCR verification, where the expressions were consistent with the sequencing analysis. The GO and KEGG pathway analyses revealed that these DE-circRNAs participate in several biological functions and signaling pathways, including glutamic synapse, neuron to neuron synapse, cell morphogenesis involved in neuron differentiation, Parkinson’s disease, axon guidance, cGMP-PKG signaling pathway, and PI3K-Akt signaling pathway. Furthermore, the KEGG analysis of the target genes predicted by DE-circRNAs indicated that the target genes predicted by mmu_circRNA_0003292, mmu_circRNA_0001320, mmu_circRNA_0005976, and mmu_circRNA_0005388 were involved in the PD-related pathway. Overall, this is the first study on the expression profile of circRNAs in the different brain regions of PD mouse model. These results might facilitate our understanding of the potential roles of circRNAs in the pathogenesis of PD. Moreover, the results also indicate that the mmu_circRNA_0003292-miRNA-132-Nr4a2 pathway might be involved in the regulation of the molecular mechanism of Parkinson’s disease.

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A Guide to the Generation of a 6-Hydroxydopamine Mouse Model of Parkinson’s Disease for the Study of Non-Motor Symptoms

Biomedicines ◽

10.3390/biomedicines9060598 ◽

2021 ◽

Vol 9 (6) ◽

pp. 598

Author(s):

Débora Masini ◽

Carina Plewnia ◽

Maëlle Bertho ◽

Nicolas Scalbert ◽

Vittorio Caggiano ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Survival Rates ◽

Dorsal Striatum ◽

Brain Regions ◽

Motor Symptoms ◽

Operative Care ◽

6 Hydroxydopamine ◽

Non Motor Symptoms

In Parkinson’s disease (PD), a large number of symptoms affecting the peripheral and central nervous system precede, develop in parallel to, the cardinal motor symptoms of the disease. The study of these conditions, which are often refractory to and may even be exacerbated by standard dopamine replacement therapies, relies on the availability of appropriate animal models. Previous work in rodents showed that injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in discrete brain regions reproduces several non-motor comorbidities commonly associated with PD, including cognitive deficits, depression, anxiety, as well as disruption of olfactory discrimination and circadian rhythm. However, the use of 6-OHDA is frequently associated with significant post-surgical mortality. Here, we describe the generation of a mouse model of PD based on bilateral injection of 6-OHDA in the dorsal striatum. We show that the survival rates of males and females subjected to this lesion differ significantly, with a much higher mortality among males, and provide a protocol of enhanced pre- and post-operative care, which nearly eliminates animal loss. We also briefly discuss the utility of this model for the study of non-motor comorbidities of PD.

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Profiling of Differentially Expressed MicroRNAs in Saliva of Parkinson's Disease Patients

Frontiers in Neurology ◽

10.3389/fneur.2021.738530 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yanyan Jiang ◽

Jing Chen ◽

Yunchuang Sun ◽

Fan Li ◽

Luhua Wei ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Microarray Analysis ◽

Target Genes ◽

Characteristic Curve ◽

Differentially Expressed ◽

Diagnostic Efficacy ◽

Mirna Microarray ◽

Candidate Mirnas ◽

Diagnostic Potential

Objective: This study aims to identify differentially expressed salivary miRNAs and validate the diagnostic potential for idiopathic Parkinson's disease (PD). Also, the disease specificity of candidate miRNAs was evaluated between PD, multiple system atrophy (MSA), and essential tremor (ET).Methods: We collected salivary samples from 50 PD, 20 ET, and 20 MSA patients, as well as 30 healthy controls (HCs). In the discovery phase, salivary miRNA microarray analysis was performed. In-silico analysis was used to investigate the target genes of differentially expressed miRNAs and clustered pathways. In validation phase, RT-qPCR was performed with samples from 30 PD patients and 30 HCs. Subsequently, we investigated candidate miRNAs in all recruited subjects. Receiver operating characteristic curve and Spearman correlation analysis was performed to determine diagnostic usefulness.Results: We identified 43 miRNAs that were differentially expressed between 5 PD patients and 5 HCs by miRNA microarray analysis. Computational analysis revealed the target genes were clustered in the pathways associated with ubiquitin protein ligase activity. The result of RT-qPCR showed that the miR-29a-3p and miR-29c-3p were found to be significantly downregulated (p = 0.004, p = 0.027), whereas the miR-6756-5p was significantly upregulated in 30 PD patients compared with 30 HCs (p = 0.032). The miR-29a-3p expression level in PD patients was significantly lower than ET patients (p = 0.035), but higher than MSA patients (p < 0.0001). The diagnostic efficacy reached a little higher when the combination of miR-29a-3p and miR-29c-3p.Conclusion: The miRNA combination of salivary miR-29a-3p and miR-29c-3p has potential to be a diagnostic biomarker for idiopathic PD.

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Bioinformatic Analysis of Circular RNA-Associated ceRNA Network Associated with Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2019/8308694 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Jiacheng Wu ◽

Shui Liu ◽

Yien Xiang ◽

Xianzhi Qu ◽

Yingjun Xie ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Pathway Analysis ◽

Target Genes ◽

Kegg Pathway ◽

Interaction Network ◽

Bioinformatic Analysis ◽

Differentially Expressed ◽

Qrt Pcr ◽

Cerna Network ◽

Kegg Pathway Analysis

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is associated with a high mortality rate and poor treatment efficacy. In an attempt to investigate the mechanisms involved in the pathogenesis of HCC, bioinformatic analysis and validation by qRT-PCR were performed. Three circRNA GEO datasets and one miRNA GEO dataset were selected for this purpose. Upon combined biological prediction, a total of 11 differentially expressed circRNAs, 15 differentially expressed miRNAs, and 560 target genes were screened to construct a circRNA-related ceRNA network. GO analysis and KEGG pathway analysis were performed for the 560 target genes. To further screen key genes, a protein-protein interaction network of the target genes was constructed using STRING, and the genes and modules with higher degree were identified by MCODE and CytoHubba plugins of Cytoscape. Subsequently, a module was screened out and subjected to GO enrichment analysis and KEGG pathway analysis. This module included eight genes, which were further screened using TCGA. Finally, UBE2L3 was selected as a key gene and the hsa_circ_0009910–miR-1261–UBE2L3 regulatory axis was established. The relative expression of the regulatory axis members was confirmed by qRT-PCR in 30 pairs of samples, including HCC tissues and adjacent nontumor tissues. The results suggested that hsa_circ_0009910, which was upregulated in HCC tissues, participates in the pathogenesis of HCC by acting as a sponge of miR-1261 to regulate the expression of UBE2L3. Overall, this study provides support for the possible mechanisms of progression in HCC.

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Neuroprotection of chicoric acid in a mouse model of Parkinson's disease involves gut microbiota and TLR4 signaling pathway

Food & Function ◽

10.1039/d1fo02216d ◽

2022 ◽

Author(s):

Ning Wang ◽

Bainian Feng ◽

Bin Hu ◽

Yuliang Cheng ◽

Yahui Guo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Gut Microbiota ◽

Signaling Pathway ◽

Echinacea Purpurea ◽

Tlr4 Signaling ◽

Chicoric Acid ◽

Purple Coneflower ◽

Tlr4 Signaling Pathway

Chicoric acid (CA), a polyphenolic acid obtained from chicory and purple coneflower (Echinacea purpurea), has been regarded as nutraceutical to combat inflammation, virus and obesity. Parkinson’s Disease (PD) is a...

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Establishment of dopaminergic neuron purification system in mice for the Parkinson’s disease study

10.21203/rs.3.rs-296465/v1 ◽

2021 ◽

Author(s):

Kit-Yeng Sheng ◽

Hideki Hayakawa ◽

Kousuke Baba ◽

Yasuyoshi Kimura ◽

Hideki Mochizuki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Protein Modification ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Sequencing Analysis ◽

Fluorescent Reporter ◽

Fatty Acid Binding ◽

Related Process

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic (DA) neurons. The key neuropathological hallmarks in the brain of patients with PD are Lewy body (LB) inclusions, consisting of misfolded α-synuclein proteins. Despite extensive efforts, the molecular link between LB inclusions and DA neurodegeneration remains elusive because of the lack of a suitable approach. Here, we aimed to establish a novel dopa-decarboxylase (Ddc) fluorescent reporter mouse model that allows the identification and collection of DA neurons using a fluorescence-activated cell sorter. Successful enrichment of Ddc-expressing cells was validated by RNA-sequencing analysis. This approach allowed us to analyze the effect of α-synuclein accumulation on the DA neuron’s transcriptome prior to neurodegeneration occurrence. We found that lipid-related process genes, followed by protein modification and degradation-related process genes, were upregulated in the α-synuclein-injected DA neurons. The activation of fatty acid-binding protein 1 (Fabp1) was particularly evident and confirmed by immunohistochemistry. Thus, our mouse model system and datasets provide a new method and insights into molecular mechanisms in PD.

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Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease

Journal of Experimental Medicine ◽

10.1084/jem.20160368 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1759-1778 ◽

Cited By ~ 181

Author(s):

Nolwen L. Rey ◽

Jennifer A. Steiner ◽

Nazia Maroof ◽

Kelvin C. Luk ◽

Zachary Madaj ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Olfactory Bulb ◽

Amyloid Fibrils ◽

Brain Regions ◽

Neural Pathways ◽

Wild Type

Parkinson’s disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed of misfolded α-synuclein (α-syn). The aggregates are believed to propagate via neural pathways following a stereotypical pattern, starting in the olfactory bulb (OB) and gut. We hypothesized that injection of fibrillar α-syn into the OB of wild-type mice would recreate the sequential progression of Lewy-like pathology, while triggering olfactory deficits. We demonstrate that injected α-syn fibrils recruit endogenous α-syn into pathological aggregates that spread transneuronally over several months, initially in the olfactory network and later in distant brain regions. The seeded inclusions contain posttranslationally modified α-syn that is Thioflavin S positive, indicative of amyloid fibrils. The spreading α-syn pathology induces progressive and specific olfactory deficits. Thus, we demonstrate that propagating α-syn pathology triggered in the OB is functionally detrimental. Collectively, we have created a mouse model of prodromal PD.

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Selenotranscriptomic Analyses Identify Signature Selenoproteins in Brain Regions in a Mouse Model of Parkinson’s Disease

PLoS ONE ◽

10.1371/journal.pone.0163372 ◽

2016 ◽

Vol 11 (9) ◽

pp. e0163372 ◽

Cited By ~ 6

Author(s):

Xiong Zhang ◽

Yang-Lie Ye ◽

Hui Zhu ◽

Sheng-Nan Sun ◽

Jing Zheng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Brain Regions

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7,8-dihydroxyflavone ameliorates motor deficits via regulating autophagy in MPTP-induced mouse model of Parkinson’s disease

Cell Death Discovery ◽

10.1038/s41420-021-00643-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Li Zuo ◽

Chunfang Dai ◽

Lilin Yi ◽

Zhifang Dong

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Signaling Pathway ◽

Dopaminergic Neurons ◽

Motor Deficits ◽

Autophagic Flux ◽

Therapeutic Effects ◽

Ampk Signaling ◽

N2a Cells

AbstractParkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra and diminished dopamine content in the striatum. Recent reports show that 7,8-dihydroxyflavone (DHF), a TrkB agonist, attenuates the α-synuclein deposition and ameliorates motor deficits. However, the underlying mechanism is unclear. In this study, we investigated whether autophagy is involved in the clearance of α-synuclein and the signaling pathway through which DHF exerts therapeutic effects. We found that the administration of DHF (5 mg/kg/day, i.p.) prevented the loss of dopaminergic neurons and improved motor functions in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, whereas these protective effects of DHF were completely blocked by autophagy inhibitor chloroquine (CQ). Further in vitro studies showed that autophagy was inhibited in N2A cells treated with 1-methyl-4-phenylpyridinium (MPP+), as reflected by a significant decrease in the expressions of autophagy marker proteins (Beclin1 and LC3II) and an increase in the expression of autophagic flux marker p62. DHF restored the impaired autophagy to control level in MPP+-treated N2A cells by inhibiting the ERK-LKB1-AMPK signaling pathway. Taken together, these results demonstrate that DHF exerts therapeutic effects in MPTP/MPP+-induced neurotoxicity by inhibiting the ERK-LKB1-AMPK signaling pathway and subsequently improving impaired autophagy.

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Serum Exosomal miRNAs as Biomarkers of Early Diagnosis and Progression in Parkinson's Disease

10.21203/rs.3.rs-220903/v1 ◽

2021 ◽

Author(s):

Qian Yang ◽

Shulei He ◽

Lu Huang ◽

Ci Shao ◽

Tiejian Nie ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Diagnosis ◽

Enrichment Analysis ◽

Functional Enrichment ◽

Differentially Expressed ◽

Healthy Controls ◽

Qrt Pcr ◽

Exosomal Mirnas ◽

Serum Exosomes

Abstract BackgroundBlood-based test for disease progression and early diagnosis of Parkinson’s disease (PD) is a long awaited but unsolved key problem in the clinic. The profiles of microRNAs (miRNAs) are regarded as potential diagnostic biomarkers in human diseases whereas the miRNAs in the periphery are susceptible to the influence of various components. MiRNAs enriched in serum exosomes have revealed disease-specific advantages for the diagnosis due to their high abundance, stability and resistant to degradation. This study aimed to screen differentially expressed exosomal miRNAs between healthy controls and PD patients to aid in diagnosis. MethodsA total of 103 healthy controls and diagnosed PD patients at different Hoehn and Yahr (H&Y) stages in Tangdu Hospital were included. In total, 185 differentially expressed miRNAs were obtained through miRNA sequencing of serum exosomes as well as edgeR and t-test analyses. Subsequently, the weighted gene co-expression network analysis (WGCNA) was utilized to identify the commonly expressed miRNAs in all stages of PD by constructing connections between modules and specifically expressed miRNAs in each stage of PD by functional enrichment analysis. The obtained miRNAs were further validated by quantitative real-time polymerase chain reaction (qRT-PCR) with peripheral blood exosomes from 30 more participants. ResultsUsing WGCNA, it was found that 4 miRNAs were commonly associated with all the stages of PD and 13 miRNAs were specifically associated with different stages of PD. Among the 17 miRNAs, 2 were commonly expressed in all the stages of PD and 5 were specifically expressed in different stages of PD via qRT-PCR; 5 were also specifically expressed in different stages of PD by WGCNA, but validation by qRT-PCR showed inconsistent results; the remaining 5 miRNAs did not exhibit significant differences by qRT-PCR. ConclusionsThis study revealed that the 7 serum exosomal miRNAs (hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-199a-3p, hsa-miR-195-5p, hsa-miR-28-5p, hsa-miR-22-5p and hsa-miR-151a-5p) we screened out may potentially be used as biomarkers for progression and early grading diagnosis of PD in the population.

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