Abstract
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.
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Data availability
The scRNAseq data generated in this study have been deposited in the GEO database under accession code GSE301050. The proteomics data generated in this study have been deposited in the ProteomeXChange database under accession code PXD075048 and in the MassIVE database under accession code MSV000101003 [https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=b41f61176673413694a7cf65448de9fe]. The metabolomics data generated in this study have been deposited in the MassIVE database under accession code MSV000098366 [https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=85492deedc7c40a39a3568287f5d398b]. Source data are provided with this paper.
Code availability
All codes used in this publication, together with the Seurat object used to generate all our scRNAseq data are available at [Ghirotto, Bruno (2025), “ENS alpha synuclein paper 2025”, Mendeley Data, V2, [https://data.mendeley.com/datasets/v8dknj466y/2].
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Acknowledgements
Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 505539112 – KFO 5024 (A01, A02, A04, B02, Z01). Further support came from the Bavarian Ministry of Science and the Arts in the framework of the ForInter network. The LC-MS system used for metabolomic analysis was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – INST 90/1048-1 FUGG. A.H. and D.B.B. were supported by the German Federal Ministry of Research, Technology and Space (BMFTR) – 031L0309A. M.S. and F.J.T.: Funded by the European Union (ERC, DeepCell − 101054957). Imaging was performed at the Optical Imaging Compentence Center Erlangen (OICE) using a DFG-funded microscope system (project number 522417173). P.G. was supported by the AI-PREDICT project (grant no. 01ZU2502) funded by the BMFTR, as well as by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through TRR 417 (Project-ID 540805631, Project S03) and SFB 1755 “CASCAID” (Project-ID 550296805, Project Z01). We thank the OICE staff, mainly Dr. Philipp Tripal and Dr. Benjamin Schmid for their technical support. We thank Daniel Beß for technical assistance with the tissue paraffin sections.
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B.G. designed the research, performed experiments, analyzed and interpreted the data, executed bioinformatics analyses, created the figures, and wrote the manuscript. L.E.G., V.R., C.J., E.G, A.G., J.G., N.C.P. performed experiments and analyzed the data. H.W. and M.F. maintained iPSC cultures. M.K., M.S. and A.H. performed bioinformatic analysis on the scRNAseq data. F.Z. generated the iPSC lines used in this study in the laboratory of J. R. Mazzulli, Northwestern University, Chicago. T.R., I.P., J.W., M.V., D.B.B., C.G., F.J.T., R.R. and M.N. provided resources and supervised the project. P.G. wrote the manuscript, analyzed and interpreted data and supervised the bioinformatics analyses. B.W. designed the research, provided resources, interpreted the data, wrote the manuscript, acquired funding and supervised the project. All authors critically reviewed and approved the final version of the manuscript.
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F.J.T. consults for Immunai Inc., CytoReason Ltd, Cellarity, BioTuring Inc., and Genbio.AI Inc., and has an ownership interest in Dermagnostix GmbH and Cellarity. The remaining authors declare no competing interests.
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Ghirotto, B., Gonçalves, L.E., Ruder, V. et al. TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71317-y
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DOI: https://doi.org/10.1038/s41467-026-71317-y
