MassIVE MSV000098371

Partial Public PXD075157

Proteomics of iPSC derived enteric neural lineages from Parkinson Disease patients

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Description

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. [doi:10.25345/C5GQ6RF47] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: iPSC ; Parkinson ; Enteric Nervous System ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Beate Winner, Friedrich Alexander Universitat Erlangen Nurnberg, Germany
Submitting User: brghirotto
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