Vimentin network dysregulation mediates neurite deficits in SNCA duplication 2 Parkinson’s patient-derived midbrain neurons [ATAC-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1256459 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33340813.fastq.gz | Fastqsanger.gz | |||
| SRR33340814.fastq.gz | Fastqsanger.gz | |||
| SRR33340815.fastq.gz | Fastqsanger.gz | |||
| SRR33340816.fastq.gz | Fastqsanger.gz | |||
| SRR33340817.fastq.gz | Fastqsanger.gz |
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Project description:Duplication of the SNCA gene (SNCADupl), linked to elevated levels of alpha-synuclein (aSyn), is a genetic cause of Parkinson's disease (PD). Our prior work with human-induced pluripotent stem cell (hiPSC)-derived midbrain neurons generated from PD SNCADupl patients identified neuritic deficits, accompanied by decreased levels of cytoskeletal element b-tubulin-III (bTubIII). To explore mechanisms underlying these effects in SNCADupl neurons, we employed CRISPR/Cas9 to generate isogenic control hiPSCs. Isogenic correction of SNCA dosage restored SNCADupl-induced neurite defects and bTubIII levels. Multi-omics analyses revealed SNCADupl-induced alterations in neuronal differentiation, with a notable downregulation of PAX6. Moreover, SNCADupl induced an upregulation of vimentin. Further characterization revealed heightened vimentin truncation, associated with altered distribution and organization. Similar changes in vimentin levels and truncation were observed in post-mortem putamen tissue from sporadic PD patients. Notably, targeting vimentin with okadaic acid and withaferin A restored bTubIII- and neurite-associated defects, suggesting its potential to prevent aSyn-mediated neuritic degeneration.
2025-07-16 | PXD063433 | Pride
Project description:Duplication of the SNCA gene (SNCADupl), linked to elevated levels of alpha-synuclein (aSyn), is a genetic cause of Parkinson's disease (PD). Our prior work with human-induced pluripotent stem cell (hiPSC)-derived midbrain neurons generated from PD SNCADupl patients identified neuritic deficits, accompanied by decreased levels of cytoskeletal element b-tubulin-III (bTubIII). To explore the underlying mechanisms for these effects in SNCADupl neurons, we employed CRISPR/Cas9 technology to generate isogenic control hiPSCs. Isogenic correction of SNCA dosage restored SNCADupl-induced neurite morphologic defects and decreased bTubIII levels. Multi-omics analyses revealed SNCADupl-induced upregulation of the cytoskeletal protein vimentin. Further characterization revealed heightened vimentin truncation, associated with altered distribution and organization. Similar changes in vimentin levels and truncation were observed in post-mortem putamen tissue from sporadic PD patients. Notably, interference with vimentin by okadaic acid and withaferin A restored bTubIII- and neurite-associated defects, suggesting that targeting vimentin potentially prevents aSyn-mediated neuritic degeneration.
2025-05-02 | GSE295832 | GEO
Project description:Duplication of the SNCA gene (SNCADupl), linked to elevated levels of alpha-synuclein (aSyn), is a genetic cause of Parkinson's disease (PD). Our prior work with human-induced pluripotent stem cell (hiPSC)-derived midbrain neurons generated from PD SNCADupl patients identified neuritic deficits, accompanied by decreased levels of cytoskeletal element b-tubulin-III (bTubIII). To explore the underlying mechanisms for these effects in SNCADupl neurons, we employed CRISPR/Cas9 technology to generate isogenic control hiPSCs. Isogenic correction of SNCA dosage restored SNCADupl-induced neurite morphologic defects and decreased bTubIII levels. Multi-omics analyses revealed SNCADupl-induced upregulation of the cytoskeletal protein vimentin. Further characterization revealed heightened vimentin truncation, associated with altered distribution and organization. Similar changes in vimentin levels and truncation were observed in post-mortem putamen tissue from sporadic PD patients. Notably, interference with vimentin by okadaic acid and withaferin A restored bTubIII- and neurite-associated defects, suggesting that targeting vimentin potentially prevents aSyn-mediated neuritic degeneration.
2025-05-02 | GSE295831 | GEO
Project description:Vimentin network dysregulation mediates neurite deficits in SNCA duplication 2 Parkinson’s patient-derived midbrain neurons [RNA-seq]
| PRJNA1256454 | ENA
Project description:To determine sensitivity of a custom 8x60k aCGH design for mosaicism of SNCA gains, a peripheral blood lymphocyte (PBL) DNA sample with a known heterozygous duplication (CN 3, or 50% increase in SNCA) was diluted with a control (wild type, wt) sample (CN 2, screened by MLPA) to create "artifical mosaics" (CN 2.4, 2.3, 2,25, 2.2, 2.15, 2.1). Dilutions, as well as the undiluted heterozygous sample, and the control, were tested, hybridised with Agilent reference DNA.
2016-02-01 | GSE71355 | GEO
Project description:SNCA, the first gene associated with Parkinson’s disease, encodes the α-synuclein protein, the predominant component within pathological inclusions termed Lewy bodies. We use 3D midbrain organoids, differentiated from human induced pluripotent stem cells derived from patients carrying a triplication of the SNCA gene and from CRISPR/Cas9 corrected isogenic control iPSCs. These human midbrain organoids recapitulate key features of α-synuclein pathology observed in the brains of patients with synucleinopathies. We used single cell RNA sequencing to characterize the cell types within these organoids. We find an equal proportion of neuronal and glial cells. The neuronal populations consist of dopmainergic, excitatory and inhibitory neurons in early and late stages of maturation as well as neural precursor cells. The glial populations consist of dividing radial glia, radial glia, astrocytes and early oligodendorcytes.
2021-11-02 | GSE186780 | GEO
Project description:Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from the SNCA mutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) with SNCA mutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into different mDA neuronal clusters. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size, and structure of aggregates in SNCA-mutant mDA neurons. By day 27 of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, in SNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated and fibrillar aggregates. When the midbrain neurons were functional, we observed impaired intracellular calcium signalling, evidenced with an increased basal calcium level and impairments in both cytosolic and mitochondrial calcium rearrangements. Once midbrain identity fully developed, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling as well as an upregulation of mitophagy and autophagy. In addition, SNCA-mutant neurons displayed pathophysiological excitability, revealed as a depolarised resting membrane potential, an increased input resistance, and impaired firing properties. Ultimately these multiple cellular stresses lead to an increase in cell death by day 62 post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
2023-03-11 | PXD035500 | Pride
Project description:Increased levels of the protein alpha-synuclein (α-syn) are associated with the development of neurodegenerative diseases like Parkinson's disease (PD). In physiological conditions, α-syn modulates synaptic plasticity, neurogenesis and neuronal survival. Here, we used a PD patient specific midbrain organoid model derived from induced pluripotent stem cells harboring a triplication in the SNCA gene to study PD-associated phenotypes. The model recapitulates the two main hallmarks of PD, which are α-syn aggregation and loss of dopaminergic neurons. Additionally, impairments in astrocyte differentiation were detected. Transcriptomics data indicate that synaptic function is impaired in PD specific midbrain organoids. This is further confirmed by alterations in synapse number and electrophysiological activity. We found that synaptic decline precedes neurodegeneration. Finally, this study substantiates that patient specific midbrain organoids allow a personalized phenotyping, which make them an interesting tool for precision medicine and drug discovery. However, its pathogenic accumulation and aggregation results in toxicity and neurodegeneration.
2024-12-02 | GSE278265 | GEO
Project description:As the second most frequent neurodegenerative disorder of old age, ParkinsonM-bM-^@M-^Ys disease (PD) can result from autosomal dominant causes like increased alpha-synuclein (SNCA) dosage, or from autosomal recessive causes like PINK1 loss-of-function. Interactions between these triggers and their potential convergence onto shared pathways are crucial to understand, but currently conflicting evidence exists. Here, we crossed previously characterized mice with A53T-SNCA overexpression and mice with PINK1 deletion to generate double mutants (DM). We studied their lifespan and behavior, together with histological and molecular anomalies at late and early ages, respectively. DM animals showed potentiated phenotypes in comparison to both single mutants (SM), with markedly reduced survival after age 450 days and strongly reduced spontaneous movements from age 3 months onwards. A considerable part of DM animals manifested progressive paralysis at ages >1 year and also exhibited protein aggregates with immunoreactivity for pSer129-SNCA, p62, and ubiquitin in spinal cord and basal brain, contrasting with absence of such features from SM. A brain proteome quantification of ubiquitination sites documented altered degradation of SNCA and the DNA-damage marker H2AX at age 18 months. Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at age 6 weeks, which were absent from SM. The observed downregulations for Dapk1, Dcaf17, Rab42 and upregulations for Dctn5, Mrpl9, Tmem181a, Xaf1 reflect changes in ubiquitination, mitochondrial / synaptic / microtubular dynamics, and DNA damage. Thus, our study confirmed that SNCA-triggered neurotoxicity is exacerbated by the absence of PINK1, and identified a novel molecular signature that is detectable early in the course of this double pathology. Factorial design comparing Pink1 knock-out/A53T-SNCA double transgenic mice with appropriate wild-type controls (129SvEv+FVB/N) in three different tissues (cerebellum, midbrain, striatum)
2014-11-04 | E-GEOD-60414 | biostudies-arrayexpress
Project description:The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD) and modulation of risk by common variation in PD has been well established through GWAS. Anticipating that a fraction of PD-associated genetic variation mediates their effects within this neuronal population, we acquired open chromatin signatures of purified embryonic mouse MB DA neurons. Correlation with >2,300 putative enhancers assayed in mice reveals enrichment for MB cis-regulatory elements (CRE), data reinforced by transgenic analyses of six additional sequences in zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directs reporter expression in catecholaminergic neurons of transgenic mice and zebrafish. Sequencing of this CRE in 986 PD patients and 992 controls reveals two common variants associated with elevated PD risk. To assess potential mechanisms of action, we identify proteins whose binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identifies a single PD-associated haplotype, containing the minor alleles of both of the aforementioned PD-risk variants. Our work posits a model for how common variation at SNCA may modulate PD risk and highlights the value of cell context-dependent guided searches for functional non-coding variation.
2018-11-14 | GSE122450 | GEO