TNFα promotes α-synuclein accumulation and impairs the malate–aspartate shuttle in patient iPSC-derived enteric neurons, driving a shift to glutamine oxidation, mitochondrial dysfunction that is partly rescued by Chicago-Sky-Blue 6B, and mirroring inflammation-associated metabolic and α-syn changes…

The study pinpoints a druggable metabolic vulnerability (malate–aspartate shuttle dysfunction) and an inflammatory driver (TNFα) in enteric neurons, demonstrates partial pharmacologic rescue, and provides a patient-derived platform that directly supports gut‑brain–targeted PD therapeutic discovery…

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.