This study shows LINC-EPS is reduced in PD patient blood and models, and that LINC-EPS protects dopaminergic neurons by scaffolding PGC-1α to its promoter to boost PGC-1α transcription, improving mitochondrial function and preventing ferroptosis, with AAV-mediated LINC-EPS and the PGC-1α activator…

Provides a blood-correlated biomarker and a mechanistic, druggable LINC-EPS→PGC-1α anti-ferroptosis axis that supports translational strategies (gene therapy/lncRNA modulation or PGC-1α activation/repurposing) for disease-modifying PD interventions.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic (DA) neuron loss and currently lacks disease-modifying treatments. We found that the long intergenic non-coding RNA LINC-EPS was markedly reduced in peripheral blood of PD patients, correlating with greater clinical severity. Similar downregulation was observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mice and 1-methyl-4-phenylpyridinium-treated DA neurons. Knockout of LINC-EPS, either systemically or specifically in DA neurons, aggravated motor deficits and DA neurodegeneration, whereas AAV-mediated overexpression rescued these phenotypes. LINC-EPS protected DA neurons by suppressing ferroptosis, acting as a scaffold that binds both PGC-1α protein and a T-box element in its promoter, thereby recruiting PGC-1α to enhance its own transcription through a positive feedback loop. This activation improved mitochondrial function, lowered reactive oxygen species, inhibited lipid peroxidation, and conferred ferroptosis resistance. Pharmacological activation of PGC-1α with ZLN005 rescued neurodegeneration in LINC-EPS-deficient PD mice. Our study identifies a novel LINC-EPS/PGC-1α axis that mitigates ferroptotic DA neuron loss and supports PGC-1α activation as a promising therapeutic strategy for PD progression.