SIX2-Mediated Microglial M2 Polarization and Exosomal miR-3470b Delivery Protect Dopaminergic Neurons in Parkinson's Disease
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ABSTRACT:
PROVIDER: PRJNA1230722 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32547779_1.fastq.gz | Fastqsanger.gz | |||
| SRR32547779_2.fastq.gz | Fastqsanger.gz | |||
| SRR32547780_1.fastq.gz | Fastqsanger.gz | |||
| SRR32547780_2.fastq.gz | Fastqsanger.gz | |||
| SRR32547781_1.fastq.gz | Fastqsanger.gz |
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Project description:Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, with neuroinflammation playing a critical role in disease progression. The transcription factor SIX2 has been identified as an anti-inflammatory factor in microglial cells; however, the underlying mechanisms remain poorly understood. In this study, we demonstrated that SIX2 overexpression protects dopaminergic cells by promoting the polarization of microglial cells from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Mechanistically, SIX2 upregulates DDIT4 expression by binding to its promoter region. DDIT4, in turn, facilitates microglial M2 polarization by inhibiting mTOR, thereby activating autophagy. Furthermore, SIX2-induced M2-polarized microglial cells secrete exosomes carrying miR-3470b. These exosomes are taken up by dopaminergic neurons, where miR-3470b inhibits GREM1 expression and enhances TGF-β signaling activity. Consequently, SIX2-mediated mechanisms prevent and restore damaged dopaminergic neurons in PD mice. Our findings reveal a novel regulatory mechanism of microglial M2 polarization and provide new insights into PD immunotherapy. Additionally, the discovery of exosome-mediated miR-3470b communication between microglia and dopaminergic neurons offers a theoretical foundation for developing exosome-based miRNA therapies.
2025-03-07 | GSE290896 | GEO
Project description:Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, with neuroinflammation playing a critical role in disease progression. The transcription factor SIX2 has been identified as an anti-inflammatory factor in microglial cells; however, the underlying mechanisms remain poorly understood. In this study, we demonstrated that SIX2 overexpression protects dopaminergic cells by promoting the polarization of microglial cells from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Mechanistically, SIX2 upregulates DDIT4 expression by binding to its promoter region. DDIT4, in turn, facilitates microglial M2 polarization by inhibiting mTOR, thereby activating autophagy. Furthermore, SIX2-induced M2-polarized microglial cells secrete exosomes carrying miR-3470b. These exosomes are taken up by dopaminergic neurons, where miR-3470b inhibits GREM1 expression and enhances TGF-β signaling activity. Consequently, SIX2-mediated mechanisms prevent and restore damaged dopaminergic neurons in PD mice. Our findings reveal a novel regulatory mechanism of microglial M2 polarization and provide new insights into PD immunotherapy. Additionally, the discovery of exosome-mediated miR-3470b communication between microglia and dopaminergic neurons offers a theoretical foundation for developing exosome-based miRNA therapies.
2025-03-08 | GSE291127 | GEO
Project description:SIX2-Mediated Microglial M2 Polarization and Exosomal miR-3470b Delivery Protect Dopaminergic Neurons in Parkinson's Disease [EV treatment]
| PRJNA1232054 | ENA
Project description:We have generated human induced Pluripotent Stem cells (hiPSc) from Parkinson's Disease patients, using retrovirus-mediated delivery of reprogramming factors. hiPSc lines have been screened using SNP array to assess chromosomal stability (alongside the fibroblast lines from which they derived), and validation of the pluripotency of the hiPSc lines is provided by Pluritest assessment of transcriptome datasets, prior to differentiation to dopaminergic neuronal clutures and downstream functional assays. Fernandes H.J.R., Hartfield E.M., Badger J., Christian H. C., Emmanoulidou E., Vowles J., Evetts S., Vekrellis K., Talbot K., Hu M.T., James W., Cowley S.A., and Wade-Martins, R. Heterozygous glucocerebrosidase mutations in Parkinson's increase autophagic demand, but decrease capacity, in induced pluripotent stem cell-derived dopaminergic neuronal cultures. submitted for publication human iPSc lines were derived from human dermal fibroblasts from 2 Parkinson's Disease patients with heterozygous glucocerebrosidase mutations (GBA N370S) mutations, and 2 idiopathic Parkinson's Disease patients. SNP datasets from the 2 control individuals used in this study have been published previously [PMID 23951090; A mature physiological cellular model of human dopaminergic neurons Hartfield E.M., Yamasaki-Mann M., Fernandes H.J., Vowles., James W.S., Cowley S.A, and Wade-Martins R. In revision]
2013-12-18 | E-GEOD-53425 | biostudies-arrayexpress
Project description:We have generated human induced Pluripotent Stem cells (hiPSc) from Parkinson's Disease patients, using retrovirus-mediated delivery of reprogramming factors. hiPSc lines have been screened using SNP array to assess chromosomal stability (alongside the fibroblast lines from which they derived), and validation of the pluripotency of the hiPSc lines is provided by Pluritest assessment of transcriptome datasets, prior to differentiation to dopaminergic neuronal clutures and downstream functional assays. human iPSc lines were derived from human dermal fibroblasts from 2 Parkinson's Disease patients with heterozygous glucocerebrosidase mutations (GBA N370S) mutations, and 2 idiopathic Parkinson's Disease patients. SNP datasets from the 2 control individuals used in this study have been published previously [PMID 23951090; A mature physiological cellular model of human dopaminergic neurons Hartfield E.M., Yamasaki-Mann M., Fernandes H.J., Vowles., James W.S., Cowley S.A, and Wade-Martins R. In revision]
2013-12-18 | E-GEOD-53424 | biostudies-arrayexpress
Project description:Objective: Parkinson's disease (PD) is part of a common type of neurodegenerative disease. AVE0991, a non-peptide analogue of Ang-(1-7), by which the progression of PD has been discovered to be ameliorated, but the specific mechanism whereby AVE0991 modulates the progression of PD remains unclear. Materials and Methods: During the study, the mice overexpressing of human α-syn(A53T) were established to simulate PD pathology, and we also constructed an in vitro model of mouse dopaminergic neurons overexpressing hα-syn(A53T). The [18F] FDG-PET/CT method was also employed to assess FDG uptake in human α-syn(A53T) overexpressing mice. Level of Lnc HOTAIRM1, miR-223-3p were detected via RT-qPCR. Flow cytometry was deployed to assay cell apoptosis. Results: AVE0991 improved behavior disorder and decreased α-syn expression in the substantia nigra in mice with Parkinson's disease. AVE0991 inhibited apoptosis of dopaminergic neurons overexpressing hα-syn(A53T) by LncRNA HOTAIRM1. MiR-223-3p binds to HOTAIRM1 as a ceRNA and directly targets α-syn. Conclusion: The angiotensin-(1–7) analogue AVE0991 targeted the HOTAIRM1/miR-223-3p axis to degrade α-synuclein in PD mice, and showed neuroprotection in vitro.
2024-11-06 | GSE244050 | GEO
Project description:Nephron progenitors in the embryonic kidney propagate while generating differentiated nephrons. However, the progenitors in mice terminally differentiate shortly after birth. We defined culture conditions to selectively propagated nephron progenitors in vitro in an undifferentiated state. To understand how expression profiles of Six2+ cells changed during culture in vitro compared with in vivo, we performed microarray analysis of Six2+ cells at E11.5 (starting material) and P0 (experiencing 8 days in vivo), and cultured Six2+ cells at E11.5 for 8 days or 19 days. Microarray analysis were performed with isolated Six2-positive nephron progenitors from transgenic mice embryo at E11.5 or P0, and cultured E11.5 Six2+ cells for 8 or 19 days in conditioned media. P0 non-progenitors represent Six2-GFP-negative cells at P0.
2016-04-14 | E-GEOD-79024 | biostudies-arrayexpress
Project description:RNA-Seq profiling of dopaminergic neurons from iPSCs of Parkinson's disease patients
| PRJEB13167 | ENA
Project description:Self-renewing undifferentiated nephron progenitors express Six2, a transcription factor that is required for their maintenance as undifferentiated progenitors. Differentiation of nephron progenitors is triggered by Wnt/b-catenin signaling. In order to understand how Six2 and Wnt signaling counteract each other, we performed ChIP-seq of Six2 and b-catenin in mesenchymal nephron progenitor cells. Nephron progenitors were FACS-isolated from BAC transgenic Six2GFPcre-positive embryonic kidneys at E16.5. For Six2 ChIP, freshly FACS isolated Six2+ cells were used. For b-catenin ChIP, FACS isolated Six2+ cells were aggregated by centrifugation at 850g for 5min and incubated in 10%FBS/DMEM containing 4uM BIO for 24hrs.
2012-09-11 | E-GEOD-39837 | biostudies-arrayexpress
Project description:The cardinal clinical features of Parkinson's disease (PD) (rigidity, rest tremor, bradykinesia, and postural instability) result from selective loss of midbrain dopaminergic neurons. More specifically, dopaminergic neurons in the substantia nigra pars compacta (SNc) are much more susceptible to damage than the adjacent dopaminergic neurons in the ventral tegmental area (VTA). This dichotomy is not only seen in human Parkinson's disease, but also in many animal models of PD, including administration of the mitochondrial toxin rotenone to rats, which replicates many of the behavioral and neuropathological features of PD. The factors underlying this selective vulnerability are unknown, but could be related to differences in neuronal circuitry, differences in glial support, or intrinsic differences between the neuronal populations of the two regions. Elucidation of these factors may lead to a greater understanding of the pathogenesis and treatment of Parkinson's disease. We will determine gene expression profiles of untreated rat SNc and VTA dopaminergic neurons using laser capture microscopy to obtain region-specific neuronal mRNA. There are intrinsic differences in gene expression between dopaminergic neurons in the rat SNc and VTA that result in greater susceptibility of SNc neurons to degeneration in experimental parkinsonism. These differences may be related to dopamine metabolism, oxidative metabolism and stress, protein aggregation, or other unforseen pathways. We will compare gene expression profiles between SNc and VTA dopaminergic neurons in normal rats. No treatment or time points will be studied in this experiment. Animals will be anesthetized, sacrificed by decapitation, and brains frozen on dry ice. Frozen sections will be collected onto glass microscope slides and rapidly immunostained for tyrosine hydroxylase to identify dopaminergic neurons. SNc and VTA neurons (approx. 200 per sample) will be isolated using laser capture microscopy. Total RNA will be extracted and poly-A RNA will be amplified using a modified Eberwine protocol. aRNA will be sent to the centers for labeling and hybridization to Affymetrix rat U34A arrays. We have confirmed with the center that our aRNA protocol is compatible with the centers amplification protocols; in fact, it is essentially identical. We will be providing a two-round amplification product to the center for labeling and hybridization. We recognize that using RNA after three rounds of amplification may decrease sensitivity for low copy number transcripts, but favor this approach versus pooling our samples (which are inherently paired) at this point. We have discussed this point in detail with the center. SNc and VTA samples from eight animals (16 samples total) will be provided to mitigate differences specific to individual animals. With the assisatnce of the center, paired t-tests will be used to determine differential expression between the two regions. Permutational t-test analysis and/or Benjamini and Hochberg analysis of expression ratios will be used to protect against multiple comparisons. Selected differentially expressed genes will be validated on separate tissue samples using quantitative RT-PCR or in situ hybridization.
2007-09-13 | E-GEOD-1837 | biostudies-arrayexpress