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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • 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

摘要

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.