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Single cell RNA sequencing data of SNCA triplication cortical organoids

ABSTRACT: Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we generated human cortical LBD models by differentiating induced pluripotent stem cells (iPSCs) from SNCA triplication LBD patients into cerebral organoids and observed increased levels of pathological α-SYN in these organoids. Single-cell RNA sequencing revealed prominent expression of the SNCA gene in excitatory neurons, which exhibited synaptic and mitochondrial dysfunction, consistent with findings in the cortex of LBD human brains. Furthermore, screening 1280 FDA-approved drugs identified four candidates, which inhibited α-SYN seeding in RT-QuIC assay, reduced α-SYN aggregation and alleviated mitochondrial dysfunction in SNCA triplication iPSC models. Our findings provide valuable insights into the development of cortical LBD models and the discovery of potential drugs targeting α-SYN aggregation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236002 | GEO | 2024/09/18

REPOSITORIES: GEO

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Project description:Kuznetsov2016(II) - α-syn aggregation kinetics in Parkinson's This theoretical model uses 2-step Finke-Watzky (FW) kinetics todescribe the production, misfolding, aggregation, transport and degradation of α-syn that may lead to Parkinson's Disease (PD). Deregulated α-syn degradation is predicted to be crucialfor PD pathogenesis. This model is described in the article: What can trigger the onset of Parkinson's disease - A modeling study based on a compartmental model of α-synuclein transport and aggregation in neurons. Kuznetsov IA, Kuznetsov AV. Math Biosci 2016 Aug; 278: 22-29 Abstract: The aim of this paper is to develop a minimal model describing events leading to the onset of Parkinson's disease (PD). The model accounts for α-synuclein (α-syn) production in the soma, transport toward the synapse, misfolding, and aggregation. The production and aggregation of polymeric α-syn is simulated using a minimalistic 2-step Finke-Watzky model. We utilized the developed model to analyze what changes in a healthy neuron are likely to lead to the onset of α-syn aggregation. We checked the effects of interruption of α-syn transport toward the synapse, entry of misfolded (infectious) α-syn into the somatic and synaptic compartments, increasing the rate of α-syn synthesis in the soma, and failure of α-syn degradation machinery. Our model suggests that failure of α-syn degradation machinery is probably the most likely cause for the onset of α-syn aggregation leading to PD. This model is hosted on BioModels Database and identified by: BIOMD0000000615. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Single cell RNA sequencing data of SNCA triplication cortical organoids

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