TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation
- Bruno Ghirotto
- Luís Eduardo Gonçalves
- Vivien Ruder
- Christina James
- Elizaveta Gerasimova
- Tania Rizo
- Holger Wend
- Michaela Farrell
- Juan Atilio Gerez
- Natalia Cecilia Prymaczok
- Merel Kuijs
- Maiia Shulman
- Anne Hartebrodt
- Iryna Prots
- Arne Gessner
- Michael Vieth
- Friederike Zunke
- Jürgen Winkler
- David B. Blumenthal
- Fabian J. Theis
- Roland Riek
- Claudia Günther
- Markus Neurath
- Pooja Gupta
- Beate Winner
2026-04-01
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.