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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids

ABSTRACT: Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids

PROVIDER: PRJNA860990 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20354605.fastq.gz	Fastqsanger.gz
	SRR20354606.fastq.gz	Fastqsanger.gz
	SRR20354607.fastq.gz	Fastqsanger.gz
	SRR20354608.fastq.gz	Fastqsanger.gz
	SRR20354609.fastq.gz	Fastqsanger.gz

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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [2]

Project description:The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited an increase in the neural progenitor population showing signs of cellular senescence. This was accompanied by a decrease in the number and complexity of dopaminergic neurons. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.

2022-07-24 | GSE208783 | GEO

Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

2022-07-24 | GSE208781 | GEO

Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

Project description:Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

| PRJNA860986 | ENA

Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [2]

Project description:Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [2]

| PRJNA860995 | ENA

Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTvsGBA]

Project description:Growing evidence indicates that Type 2 diabetes (T2D) is associated with an increased risk of developing PD Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism, and survival. To better understand the importance of insulin signalling in the human midbrain, which is the most affected brain region in PD, we expose IPSC-derived human midbrain organoids from healthy individuals and GBA-N370S mutation-carrying PD patients to either high insulin concentrations, promoting insulin resistance, or to more physiological insulin concentrations restoring normal insulin signalling function. We are able to show that insulin resistance compromises dopaminergic neuron and dopamine levels in the midbrain organoids of healthy donors. Moreover, insulin-resistant organoids display diminished neuronal activity and reduced metabolic efficiency. Furthermore, our findings demonstrate FOXO1 role in GBA-PD phenotype severity and show the potential beneficial effects of the anti-diabetic drug Pioglitazone in GBA-PD treatment. Overall, our results highlight insulin resistance as a significant target in PD prevention and disease-modifying therapy.

2024-10-01 | GSE237115 | GEO

Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTs]

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Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids [scRNA-Seq]

Project description:Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

2023-10-28 | GSE241631 | GEO

Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids [RNA-Seq]

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Single-cell transcriptomics and in vitro lineage tracing reveals differential susceptibility of human iPSC-derived midbrain dopaminergic neurons in a cellular model of Parkinson’s disease.

Project description:Advances in stem cell technologies open up new avenues for modelling development and diseases. The success of these pursuits however rely on the use of cells most relevant to those targeted by the disease of interest, for example, midbrain dopaminergic neurons for Parkinson’s disease. In the present study, we report the generation of a human induced pluripotent stem cell (iPSC) line capable of purifying and tracing nascent midbrain dopaminergic progenitors and their differentiated progeny via the expression of a Blue Fluorescent Protein (BFP). This was achieved by CRISPR/Cas9 assisted knock-in of BFP and Cre into the safe harbour locus AAVS1 and an early midbrain dopaminergic lineage marker gene LMX1A, respectively. Immunocytochemical analysis and single cell RNA sequencing of iPSC-derived neural cultures confirms developmental recapitulation of the human fetal midbrain and high quality midbrain cells. By modelling Parkinson’s disease-related drug toxicity using 1-Methyl-4-phenylpyridinium (MPP+), we showed preferential reduction of BFP+ cells, a finding demonstrated independently by cell death assays and single cell transcriptomic analysis of MPP+ treated neural cultures. Together, these results highlight the importance of disease relevant cell type in stem cell modelling.

2023-12-08 | GSE249360 | GEO

Single-cell transcriptomics and in vitro lineage tracing reveals differential susceptibility of human iPSC-derived midbrain dopaminergic neurons in a cellular model of Parkinson’s disease

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