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Necroptosis inhibition protects from dopaminergic neuronal cell death in OPA1 mutant Parkinson’s disease patient neurons and MPTP treated mice

ABSTRACT: Necroptosis inhibition protects from dopaminergic neuronal cell death in OPA1 mutant Parkinson’s disease patient neurons and MPTP treated mice

PROVIDER: PRJNA430219 | ENA |

REPOSITORIES: ENA

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Necroptosis inhibition protects from dopaminergic neuronal cell death in OPA1 mutant Parkinson’s disease patient neurons and MPTP treated mice

Project description:Dysfunctions in mitochondria dynamics and metabolism are common pathological processes associated with Parkinson’s disease (PD). Recently, it was shown that an inherited form of PD and dementia is caused by new mutations in the OPA1 gene, which encodes for a key player of mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1 mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both the early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a promising therapeutic target for PD.

2019-01-16 | GSE109228 | GEO

A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease

Project description:The degenerative process in Parkinson’s disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. At present study, we generated a primate model of PD by carotid artery injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP and sampled substantia nigra and putamen of macaque for single cell sequencing analysis.

2023-11-19 | E-MTAB-13437 | biostudies-arrayexpress

Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson’s disease

Project description:We performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and Parkinson’s disease (PD) patients.

2022-06-17 | GSE206308 | GEO

Genotype data from induced Pluripotent Stem cells from OPA1 Haploinsufficiency patients

Project description:We have generated human induced Pluripotent Stem cells (hiPSc) from two individuals with OPA1 haploinsufficiency, and one control donor, using Sendai virus-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. Mitochondrial fragmentation in iPSC-derived dopaminergic neurons with OPA1 haploinsufficiency underpins increased apoptosis and syndromic Parkinsonism.

2017-02-03 | GSE94432 | GEO

Gene expression data from induced Pluripotent Stem cells from OPA1 Haploinsufficiency patients

2017-02-03 | GSE94425 | GEO

Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

Project description:In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed.

2021-06-30 | GSE169755 | GEO

Identification of salsolinol as an RNA m6A methylation inducer that mediates dopaminergic neuronal death by regulating YAP1 and autophagy

Project description:Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that can cause neurotoxicity because of its structural similarity with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an environmental toxin that causes Parkinson’s disease (PD). However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal can significantly enhance the global level of N6-methyladenosine (m6A) mRNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylase FTO (fat mass and obesity-associated protein) and ALKBH5 (alkB homolog 5). The results of the RNA-Seq analysis showed that Sal can exert a neurotoxic effect by regulating the Hippo signaling pathway through RNA methylation. We found that m6A reader YTHDF2 (YTH domain-containing family protein 2) promoted the degradation of m6A-containing YAP1 (Yes-associated protein 1) mRNA, which is a downstream key effector in the Hippo pathway. Additionally, the downregulation of YAP1 can also promote autophagy, indicating that the inter-regulation of YAP1 and autophagy can lead to neurotoxicity. Our findings showed the effect of Sal on m6A RNA methylation and revealed that Sal can act as an RNA modification inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provided greater insights into the neurotoxic effects of catechol isoquinolines and might be used as a reference for further assessing the involvement of RNA methylation in the pathogenesis of PD.

2023-12-04 | GSE249025 | GEO

RNA-SEQ profiling of dopaminergic neurons from the mid-brain of mice that received intraperitoneal injections of MPTP

Project description:RNA-SEQ of dopaminergic neurons from the mid-brain of mice that received one daily intraperitoneal injection of MPTP-HCl (30 mg/kg free base per day) or saline for five consecutive days. Samples were taken 4 days. Murine midbrain dopaminergic neurons that were treated with MPTP-HCl

2015-07-27 | E-GEOD-54795 | biostudies-arrayexpress

Transcriptomics analysis of human iPSC-derived dopaminergic neurons reveals a novel model for sporadic Parkinson’s disease

Project description:First, we differentiated human iPSCs into dopaminergic neurons. To reproduce and to study sporadic PD, the cells were subsequently exposed to increasing concentrations of the neurotoxin MPP+, which is considered the standard for experimentally inducing Parkinsonism. Resulting cells were examined using temporal transcriptomics analysis at various time-points after 24h of exposure. The transcriptomics analysis revealed a strong time- and dose-dependent response with genes overrepresented across pathways involved in PD etiology such as “Parkinson’s Disease”, “Dopaminergic signaling” and “calcium signaling”.

2022-07-07 | GSE196190 | GEO

Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

Project description:Dopaminergic neurons of the substantia nigra pars compacta selectively and progressively degenerate in Parkinson’s disease. Until now, molecular analyses of dopaminergic neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in Parkinson’s disease, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of LMD-dissected neurons from substantia nigra pars compacta in Parkinson’s disease.

2021-12-30 | PXD024748 | Pride

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