TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation
TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation
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Original abstract
Gastrointestinal dysfunction often precedes motor symptoms in Parkinson's disease (PD), suggesting the enteric nervous system (ENS) is central to early pathogenesis. How alpha-synuclein contributes to ENS dysfunction, and how inflammation modulates this, remains unclear. Here we show that Tumor Necrosis Factor alpha enhances alpha-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 alpha-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.