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Gene expression profile of healthy control organoids, a Parkinson disease patient specific midbrain organoid carrying a triplication in the SNCA gene and two healthy control organoids co-cultured with either healthy or PD hindbrain organoids

ABSTRACT: Gene expression profile of healthy control organoids, a Parkinson disease patient specific midbrain organoid carrying a triplication in the SNCA gene and two healthy control organoids co-cultured with either healthy or PD hindbrain organoids

PROVIDER: PRJNA1153030 | ENA |

REPOSITORIES: ENA

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Gene expression profile of healthy control organoids, a Parkinson disease patient specific midbrain organoid carrying a triplication in the SNCA gene and two healthy control organoids co-cultured with either healthy or PD hindbrain organoids

Project description:Single nuclei RNAseq was used to characterize the cell diversity in healthy control hindbrain organoids, as well as in PD midbrain organoids. Sequencing of healthy midbrain organoids after co-culture with either healthy or PD hinbrain organoids was used to compare the influence of the healthy versus the disease hindbrain context to the healthy midbrain model.

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Single cell RNA sequencing data of SNCA triplication cortical organoids

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Single cell RNA sequencing data of SNCA triplication cortical organoids

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Single cell RNA sequencing analysis of midbrain organoids with SNCA gene triplication modeling key features of synuclienopathy

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.

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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.

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Midbrain organoids with an <i>SNCA</i> gene triplication model key features of synucleinopathy.

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. The presence of Lewy bodies is one of the classical hallmarks found in the brain of patients with Parkinson's disease, and Lewy bodies have also been observed in patients with other synucleinopathies. However, the study of α-synuclein pathology in cells has relied largely on two-dimensional culture models, which typically lack the cellular diversity and complex spatial environment found in the brain. Here, to address this gap, we use three-dimensional 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. In particular, we find that SNCA triplication human midbrain organoids express elevated levels of α-synuclein and exhibit an age-dependent increase in α-synuclein aggregation, manifested by the presence of both oligomeric and phosphorylated forms of α-synuclein. These phosphorylated α-synuclein aggregates were found in both neurons and glial cells and their time-dependent accumulation correlated with a selective reduction in dopaminergic neuron numbers. Thus, human midbrain organoids from patients carrying SNCA gene multiplication can reliably model key pathological features of Parkinson's disease and provide a powerful system to study the pathogenesis of synucleinopathies.

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

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