TNF-α disrupts the malate-aspartate shuttle, driving metabolic rewiring in iPSC-derived enteric neural lineages from Parkinson's Disease patients.

ABSTRACT: Gastrointestinal (GI) dysfunction emerges years before motor symptoms in Parkinson's disease (PD), implicating the enteric nervous system (ENS) in early disease progression. However, the mechanisms linking the PD hallmark protein, α-synuclein (α-syn), to ENS dysfunction - and whether these mechanisms are influenced by inflammation - remains elusive. Using iPSC-derived enteric neural lineages from patients with α-syn triplications, we reveal that TNF-α increases mitochondrial-α-syn interactions, disrupts the malate-aspartate shuttle, and forces a metabolic shift toward glutamine oxidation. These alterations drive mitochondrial dysfunction, characterizing metabolic impairment under cytokine stress. Interestingly, targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial

SUBMITTER: Ghirotto B 

PROVIDER: S-EPMC11974853 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature