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Ghirotto, B.* ; Gonçalves, L.E.* ; Ruder, V.* ; James, C.* ; Gerasimova, E.* ; Rizo, T.* ; Wend, H.* ; Farrell, M.* ; Gerez, J.A.* ; Prymaczok, N.C.* ; Kuijs, M. ; Shulman, M. ; Hartebrodt, A.* ; Prots, I.* ; Gessner, A.* ; Vieth, M.* ; Zunke, F.* ; Winkler, J.* ; Blumenthal, D.B.* ; Theis, F.J. ; Riek, R.* ; Günther, C.* ; Neurath, M.* ; Gupta, P.* ; Winner, B.*

TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation.

Nat. Commun. 17:3217 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Gastrointestinal dysfunction often precedes motor symptoms in Parkinson's disease (PD), suggesting the enteric nervous system (ENS) is central to early pathogenesis. How α-synuclein contributes to ENS dysfunction, and how inflammation modulates this, remains unclear. Here we show that Tumor Necrosis Factor alpha enhances α-synuclein accumulation in induced pluripotent stem cell-derived enteric neurons and glia, and impairs the malate-aspartate shuttle, a key pathway for mitochondrial energy production. This drives a metabolic shift toward glutamine oxidation in patient cells. This metabolic impairment reduces overall mitochondrial function, which is partially rescued by the neuroprotective compound Chicago-Sky-Blue 6B. Furthermore, transcriptomic and histological analyses of human gut tissue from inflammatory bowel disease patients reveal that inflammation-associated metabolic suppression and α-synuclein upregulation occur beyond PD, representing general hallmarks of intestinal inflammation. These findings highlight a conserved metabolic vulnerability in the ENS and establish patient-derived enteric lineages as a robust platform to model inflammatory ENS pathology.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nervous-system; Synuclein; Lineages; Cells
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 17, Issue: 1, Pages: , Article Number: 3217 Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants Funded by the European Union (ERC, DeepCell - 101054957)
Deutsche Forschungsgemeinschaft (German Research Foundation)
Bundesministerium fr Bildung und Forschung (Federal Ministry of Education and Research)