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

Ghirotto B, Gonçalves LE, Ruder V, James C, Gerasimova E, Rizo T, Wend H, Farrell M, Gerez JA, Prymaczok NC, Kuijs M, Shulman M, Hartebrodt A, Prots I, Geßner A, Vieth M, Zunke F, Winkler J, Blumenthal DB, Theis FJ, Riek R, Günther C, Neurath M, Gupta P, Winner B (2026)

Publication Language: English

Publication Type: Journal article

Publication year: 2026

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 17

Journal Issue: 1

DOI: 10.1038/s41467-026-71317-y

Open Access Link: https://www.nature.com/articles/s41467-026-71317-y

Abstract

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.

Authors with CRIS profile

Bruno Ghirotto Nunes Professur für Stammzell-Modelle seltener neuraler Erkrankungen Christina James Professur für Stammzell-Modelle seltener neuraler Erkrankungen Elizaveta Gerasimova Department of Operative Dentistry and Periodontology Tania Rizo Garza Professur für Stammzell-Modelle seltener neuraler Erkrankungen Anne Hartebrodt Professur für Biomedical Network Science Iryna Prots Department of Operative Dentistry and Periodontology Arne Geßner Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Michael Vieth Institute of Pathology Jürgen Winkler Professur für Molekulare Neurologie David B. Blumenthal Professur für Biomedical Network Science Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Pooja Gupta Professur für Stammzell-Modelle seltener neuraler Erkrankungen Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich CH Switzerland (CH) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE)

How to cite

APA:

Ghirotto, B., Gonçalves, L.E., Ruder, V., James, C., Gerasimova, E., Rizo, T.,... Winner, B. (2026). TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-71317-y

MLA:

Ghirotto, Bruno, et al. "TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation." Nature Communications 17.1 (2026).

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