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Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patient

ABSTRACT: Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patient

PROVIDER: PRJNA856043 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19994439.fastq.gz	Fastqsanger.gz
	SRR19994440.fastq.gz	Fastqsanger.gz
	SRR19994441.fastq.gz	Fastqsanger.gz
	SRR19994442.fastq.gz	Fastqsanger.gz
	SRR19994443.fastq.gz	Fastqsanger.gz

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Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patient

Project description:Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology. RNA sequencing

2023-11-20 | GSE207533 | GEO

Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson's disease patients.

Project description:Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.

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Modelling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids

Project description:Recent advances in generating 3 dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson’s disease-associated LRRK2 G2019S mutation. LRRK2-G2019S midbrain organoids derived from LRRK2 targeted human iPSCs in vitro have LRRK2-associated sporadic Parkinson's disease phenotypes. Midbrain-like 3D organoids expressing LRRK2-G2019S showed dynamic changes in globle gene expression.

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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.

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

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Project description:Use of patient specific models, such as midbrain organoids, have shown to be valuable tools to models Parkinson’s disease as well as to identify novel pathological cellular and molecular mechanisms. In here, we used single cell RNA sequencing analysis of 60 day old midbrain organoids obtained from a Parkinson’s disease patient carrying the p.R272Q Miro1 mutation, its isogenic control and a healthy control to explore the effect of RhoT1 gene in different cellular populations present within the midbrain organoids (e.g. dopaminergic neurons, astrocytes) and the subsequent effect on the PD pathology.

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Modelling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids

Project description:Modelling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids

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Parkinson’s Disease Genetic Risk in a Midbrain Neuronal Cell Line

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Synaptic decline precedes dopaminergic neuronal loss in human midbrain organoids harboring a triplication of the SNCA gene

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

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