Pathological effects of SARS-CoV-2 and α-synuclein preformed fibril in hESC-derived dopaminergic neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA872933 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21203223_1.fastq.gz | Fastqsanger.gz | |||
| SRR21203223_2.fastq.gz | Fastqsanger.gz | |||
| SRR21203224_1.fastq.gz | Fastqsanger.gz | |||
| SRR21203224_2.fastq.gz | Fastqsanger.gz | |||
| SRR21203225_1.fastq.gz | Fastqsanger.gz |
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Project description:Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons. Recent studies suggested the association of zinc finger protein 184 (ZNF184) with PD. However, the functional role of ZNF184 in PD pathogenesis remains unclear. Therefore, we aimed to confirm this association and the effects of ZNF184 in a mouse model of PD and human patients with PD.We found that ZNF184 levels were decreased in the substantia nigra (SN) of α-synuclein preformed fibril (α-syn PFF)-injected mice and cells treated with PD toxins. Furthermore, ZNF184 was reduced in the cortex and SN of patients with PD, suggesting an association between ZNF184 and PD pathogenesis. In ZNF184-overexpressing cells, RNA-sequencing analysis revealed significant alterations in several protein-coding genes including interleukin enhancer binding factor 3 (ILF3). Bioinformatic analysis identified potential ZNF184 binding motifs within the ILF3 promoter, and ZNF184 occupancy was confirmed. Since ILF3 inhibits the biogenesis of microRNA-7 (miR-7), which regulates α-synuclein aggregation, we administered the miR-7 inducer, scutellarin to α-syn PFF-injected mice, preventing dopaminergic neuron and reinstating motor abilities. Our findings suggest that ZNF184 promotes miR-7 upregulation by suppressing ILF3 transcription, revealing a novel pathway that could serve as a promising therapeutic target for the treatment of PD.
2024-11-20 | GSE282345 | GEO
Project description:Progression Parkinson’s disease (PD) has been strongly correlated to concurrent virus infection such as herpes virus, Helicobacter pylori, hepatitis C, and pneumococcus and the concurrent immune response in the brain. However, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the onset and progression of PD is yet to be investigated. As the pandemic is getting closer to being under control and majority of the population in the world will have been infected with SARS-CoV-2, there will be a huge need for uncovering the unknown, possible neurological sequelae of SARS-CoV-2 infection. Here we report that SARS-CoV-2 infection increased the susceptibility of DA neurons to PFF-induced cell death while PFF or SARS-CoV-2 alone did not exert a cytotoxic effect on dopaminergic (DA) neurons. RNA sequencing data revealed mechanistic investigations that SARS-CoV-2, in vitro, increased susceptibility to PFF-induced PD-like pathology including changes in expression of signaling molecules in apoptosis, autophagy, oxidative stress, and mitochondrial function. Thus, our study provides a previously unappreciated paradigm that SARS-CoV-2 infection persists in the brain and increases susceptibility to neurodegenerative diseases such as PD via continuous inflammatory response as a long-term sequela.
2023-08-24 | GSE211934 | GEO
Project description:Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple system atrophy (MSA). The diseases are characterized by the abnormal deposition and aggregation of a-synuclein and neuroinflammation. Recent studies have demonstrated the existence of structurally distinct a-synuclein aggregates in this group of the diseases. While the correlation between specific forms of a-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct a-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia) were treated with a-synuclein polymorphs including EGCG stabilized a-synuclein oligomers (EO), kinetically stable a-synuclein oligomers (KSO), dopamine stabilized a-synuclein oligomers (DO), a-synuclein preformed fibrils (PFF), sonicated a-synuclein preformed fibrils (sPFF), and matured a-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable a-synuclein oligomers and matured a-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct a-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable a-synuclein oligomers induce the activities of TLR2 and 4, and sonicated a-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct a-synuclein polymorphs have likewise distinct neuroinflammatory properties.
2026-01-21 | GSE305401 | GEO
Project description:Zinc finger protein 184 prevents α-synuclein preformed fibril-mediated neurodegeneration through the interleukin enhancer binding factor 3-microRNA-7 pathway
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Project description:Although-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with -synuclein triplication or controls where endogenous -synuclein was imprinted into synthetic or disease-relevant conformations. We used -synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in -synuclein levels in -synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in -synuclein gene expression. Progressive neuronal loss was observed only in -synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of -synuclein triplication revealed that intraneuronal-synuclein levels solely and sufficiently explained vulnerability to neuronal death. Proximity-dependent biotinylation in living cells identified 56 differentially interacting proteins with endogenously assembled -synuclein including evasion of Parkinson’s disease-associated deglycase DJ-1 by aggregates triggered with brain amplified fibrils. Knockout of DJ-1 and related glyoxalase-1 in cell lines increased -synuclein aggregation. Similarly, methylglyoxal treatment or CRISPR/Cas9 knockout of DJ-1 in iPSC-derived dopaminergic neurons enhanced fibril-induced aggregation and cell death. Thus, toxicity of -synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our results define parameters for iPSC-based modellingof -synuclein pathology using brain amplified fibrils and demonstrate how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.
2021-04-19 | PXD024198 | Pride
Project description:Background: Parkinson’s disease is a progressive neurodegenerative disorder characterized by the presence of pathological aggregation of the protein -synuclein and the loss of dopaminergic neurons in the substantia nigra. There is evidence that misfolding and propagation of -synuclein aggregates through networks of interconnected neurons is responsible for the pathological spread and progressive neuron loss. However, in vivo models demonstrating such pathological progression remain elusive. Results: This study utilizes a zebrafish model in order to interrogate the mechanisms of -synuclein toxicity and spread. We describe the development of a zebrafish model of neuronal human -synuclein overexpression that causes, in young fish, behavioral and neuronal changes as well as microglia activation. In aged fish, -synuclein expression induces a slow but progressive pathological phenotype manifesting in neuron loss within the gut and the CNS. This model is further utilized to seed gut pathology by incorporating a novel method of feeding human -synuclein preformed fibrils in order to initiate protein misfolding at an early age. The combination of neuronal expression of -synuclein and the exogenous addition of misfolded protein facilitates the development of brain pathology and subsequent neuron loss in the CNS. In addition to the pathological alterations induced with the fibril feeding model, genetic changes were identified by single cell RNA sequencing. These transcriptomic changes resulted in pathway alteration that implicate neurodegenerative disease processes. Conclusion: This model of -synuclein pathology is useful for understanding mechanisms underlying disease initiation and can replicate the progressive development of pathological synuclein accumulation. It has the potential to induce neuron to neuron spread and also offers a way to explore what interventions may prevent such pathological progression.
2026-01-17 | GSE316223 | GEO
Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.
2020-09-02 | GSE149632 | GEO
Project description:Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous a-synuclein was imprinted into synthetic or disease-relevant conformations. We used a-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in a-synuclein levels in a-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in a-synuclein gene expression. Progressive neuronal loss was observed only in a-synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of a-synuclein triplication revealed that intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death
2021-04-13 | GSE171999 | GEO
Project description:Physical activity is thought to provide clinical benefit in Parkinson’s diseas (PD). Irisin is a blood-brain barrier permeable exercise-induced polypeptide secreted by muscle that mediates, in part, the beneficial effects of exercise. Here we show that irisin prevents pathologic -synuclein (-syn) induced neurodegeneration in the -syn preformed fibril mouse model of sporadic PD. Intravenous delivery of adenoviral irisin in vivo after the stereotaxic intrastriatal injection of -syn pre-formed fibrils reduced the formation of pathologic -syn and prevented the loss of dopamine neurons and reductions in striatal dopamine. Irisin also reduced the -syn pre-formed fibril induced motor deficits as assessed by the pole test and grip strength test. Administration of recombinant irisin in primary cortical neurons prevented pathologic -syn toxicity. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic -syn by enhancing endolysosomal degradation of pathologic -syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.
2022-10-15 | PXD032670 | Pride
Project description:Previous studies demonstrated that dopaminergic neurons in the substantia nigra pars compacta (SNpc) of mice with null mutations for genes encoding a-synuclein and/or y-synuclein are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. An original straightforward interpretation of these results was that these proteins are directly involved in the mechanism of MPTP-induced degeneration and this view has become commonly accepted. Here we provide evidence that a plausible explanation of this resistance is not the absence of these synucleins per se but their substitution on the membrane of synaptic vesicles by the third member of the family, b-synuclein. Dopaminergic neurons of mice lacking b-synuclein singularly or in combination with the loss of other synucleins, were sensitive to the toxic effect of MPTP. Dopamine uptake by synaptic vesicles isolated from the striatum of triple a/b/y-synuclein deficient mice was significantly reduced, while reintroduction of b-synuclein either in vivo or in vitro reversed this effect. Proteomic analysis of complexes formed on the surface of synuclein-free synaptic vesicles after addition of recombinant b-synuclein identified multiple integral constituents of these vesicles as well as typically cytosolic proteins, including key enzymes involved in dopamine synthesis, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). Therefore, b-synuclein plays a scaffolding role for the assembly of molecular complexes that enhance the ability of synaptic vesicles to uptake and sequester dopamine and other structurally similar molecules, including MPP+. Deficiency of b-synuclein therefore results in the accumulation of MPP+ in the cytosol, where it imposes a damaging effect on presynaptic terminals and ultimately the destruction of dopaminergic neurons.
2021-11-29 | PXD027667 | Pride