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Metabolomics of iPSC derived enteric neural lineages from Parkinson Disease patients challenged with TNF alpha

ABSTRACT: Gastrointestinal (GI) dysfunction precedes motor symptoms in Parkinson disease (PD), implicating the enteric nervous system (ENS) in early disease pathogenesis. However, how the PD-associated protein alpha synuclein (alpha syn) contributes to ENS dysfunction, and whether this is influenced by inflammation, remains unresolved. Here, we show that tumor necrosis factor alpha (TNF alpha) increases alpha syn accumulation at mitochondria, disrupts the malate-aspartate shuttle (MAS), and induces a metabolic shift toward glutamine oxidation in iPSC derived enteric neural lineages (ENLs) from PD patients carrying alpha syn gene triplications. This metabolic rewiring leads to mitochondrial dysfunction, NAD+ depletion, and oxidative stress. Targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial function and reverses TNF alpha induced metabolic impairment. Combined transcriptomic and histological analyses of human gut tissue show that inflammation-associated MAS suppression and alpha syn upregulation are not confined to PD but are general hallmarks of intestinal inflammation. These findings highlight a conserved metabolic vulnerability in the ENS and establish iPSC ENLs as a powerful platform for modeling early inflammatory disease mechanisms.

INSTRUMENT(S): Dionex instrument model

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Beate Winner

PROVIDER: MSV000098366 | MassIVE | Fri Jun 27 12:47:00 BST 2025

REPOSITORIES: MassIVE

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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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Metabolomics of iPSC derived enteric neural lineages from Parkinson Disease patients challenged with TNF alpha

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