TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation.
Overview
15 affiliations
- Department of Stem Cell Biology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- International Max Planck Research School in Physics and Medicine, Erlangen, Germany
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Dental Clinic 1-Department of Operative Dentistry and Periodontology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Present Address: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO USA
- Institute of Molecular Physical Sciences, ETH Zürich, Zürich, Switzerland
- Institute of Computational Biology, Helmholtz Center, Munich, Germany
- TUM, School of Computation, Information and Technology, Technical University of Munich, Munich, Germany
- TUM School of Life Sciences, Technical University of Munich, Munich, Germany
- Biomedical Network Science Lab, Department Artificial Intelligence in Biomedical Engineering (AIBE), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Center of Rare Diseases Erlangen (ZSEER), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
No file of the authors' code could be read here: it is described below, and read at its source.
data.mendeley.com/datasets/v8dknj466y
Availability: 1 check, the latest on 28 September 2026: the link answers (HTTP 200)
- 28 September 2026: the link answers (HTTP 200)
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://
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE301050, at NCBI GEO; found in “Data availability”
- massive.ucsd.edu/
proteosafe/ , at massive.ucsd.edu; found in “Data availability”dataset.jsp - pride:PXD075048, at PRIDE; found in “Data availability”
Data Availability Statement
The scRNAseq data generated in this study have been deposited in the GEO database under accession code GSE301050 (https://
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://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 25 authors, 2 keywords, 18 MeSH terms, 3 funders, 85 references, 20 RRIDs.
Cite
This paper
Ghirotto, B., Gonçalves, L. E., Ruder, V., James, C., Gerasimova, E., Rizo, T., Wend, H., Farrell, M., Gerez, J. A., Prymaczok, N. C., Kuijs, M., Shulman, M., Hartebrodt, A., Prots, I., Gessner, A., Vieth, M., Zunke, F., Winkler, J., Blumenthal, D. B., . . . Winner, B. (2026). TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation. Nature communications, 17(1), 3217. https://
BibTeX
@article{ghirotto2026tnf
author = {Ghirotto, Bruno and Gonçalves, Luís Eduardo and Ruder, Vivien and James, Christina and Gerasimova, Elizaveta and Rizo, Tania and Wend, Holger and Farrell, Michaela and Gerez, Juan Atilio and Prymaczok, Natalia Cecilia and Kuijs, Merel and Shulman, Maiia and Hartebrodt, Anne and Prots, Iryna and Gessner, Arne and Vieth, Michael and Zunke, Friederike and Winkler, Jürgen and Blumenthal, David B and Theis, Fabian J and Riek, Roland and Günther, Claudia and Neurath, Markus and Gupta, Pooja and Winner, Beate},
title = {{TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation}},
journal = {Nature communications},
year = {2026},
month = apr,
volume = {17},
number = {1},
pages = {3217},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/
url = {https://
pmid = {41922384},
pmcid = {PMC13057073}
}
RIS
TY - JOUR
AU - Ghirotto, Bruno
AU - Gonçalves, Luís Eduardo
AU - Ruder, Vivien
AU - James, Christina
AU - Gerasimova, Elizaveta
AU - Rizo, Tania
AU - Wend, Holger
AU - Farrell, Michaela
AU - Gerez, Juan Atilio
AU - Prymaczok, Natalia Cecilia
AU - Kuijs, Merel
AU - Shulman, Maiia
AU - Hartebrodt, Anne
AU - Prots, Iryna
AU - Gessner, Arne
AU - Vieth, Michael
AU - Zunke, Friederike
AU - Winkler, Jürgen
AU - Blumenthal, David B
AU - Theis, Fabian J
AU - Riek, Roland
AU - Günther, Claudia
AU - Neurath, Markus
AU - Gupta, Pooja
AU - Winner, Beate
TI - TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/
VL - 17
IS - 1
SP - 3217
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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