TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation
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
- Claudia Günther (ORCID: https://orcid.org/0000-0001-8360-3525)
- Arne Gessner (ORCID: https://orcid.org/0000-0002-1729-4231)
- Maiia Shulman (ORCID: https://orcid.org/0009-0006-6308-1997)
- Juan Gerez (ORCID: https://orcid.org/0000-0002-3326-2897)
- Iryna Prots (ORCID: https://orcid.org/0000-0001-9561-0909)
- Natalia Cecilia Prymaczok
- Michaela Farrell
- Tania Rizo (ORCID: https://orcid.org/0000-0003-4922-7719)
- Friederike Zunke (ORCID: https://orcid.org/0000-0002-0408-6388)
- Christina James (ORCID: https://orcid.org/0000-0002-7443-929X)
- Anne Hartebrodt (ORCID: https://orcid.org/0000-0002-9172-3137)
- Pooja Gupta (ORCID: https://orcid.org/0009-0009-3328-5157)
- Holger Wend
- Fabian Joachim Theis (ORCID: https://orcid.org/0000-0002-2419-1943)
- Roland Riek (ORCID: https://orcid.org/0000-0002-6333-066X)
- David B. Blumenthal (ORCID: https://orcid.org/0000-0001-8651-750X)
- Elizaveta Gerasimova (ORCID: https://orcid.org/0000-0003-1294-1919)
- Merel Kuijs (ORCID: https://orcid.org/0000-0003-4193-1138)
- B. Ghirotto
- Vivien Ruder
- Luís Eduardo Gonçalves
- Jürgen Winkler
- B. Winner
- M Vieth
- Markus Neurath
Institutions
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Colorado Boulder (US)
- Bayreuth Medical Center (DE)
- Helmholtz Zentrum München (DE)
- ETH Zurich (CH)
- Universitätsklinikum Erlangen (DE)
- Max Planck Institute for the Science of Light (DE)
- Comprehensive Cancer Center Erlangen (DE)
- Technical University of Munich (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1038/s41467-026-71317-y
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- International Max Planck Research School for Environmental, Cellular and Molecular Microbiology
- European Commission
- Friedrich-Alexander-Universität Erlangen-Nürnberg
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Eidgenössische Technische Hochschule Zürich
- Technische Universität München