Blood-based biomarkers of ferroptosis in Parkinson's disease

BACKGROUND: As Parkinson's disease progresses, patients require second-line treatments such as subthalamic stimulation, the benefits of which may be diminished by the onset of non-dopaminergic axial motor and cognitive disorders. This study aimed to identify blood biomarkers of ferroptosis for predicting the progression of Parkinson's disease at the stage of L-DOPA-related complications. METHODS: We analyzed 598 blood samples from patients with PD enrolled in the French multicentric PREDISTIM study. Neurofilament light chain, 4-hydroxy-2-nonenal, glutathione peroxidase activity, ferritin, alpha-synuclein and selenium levels were determined by electrochemiluminescence, ELISA or inductively coupled plasma mass spectrometry. We assessed three single-nucleotide polymorphisms in ACSL4 and GPX4 genes, two key players in ferroptosis. Overall clinical outcomes were evaluated at baseline and one-year post-surgery. RESULTS: ), selenium concentration (p = 0.033) and the rs7887981 in the ACSL4 gene (p = 0.033). Milder cognitive problems were correlated with the rs139736475 in ACSL4 (p = 0.028). One-year post-surgery, change in UPDRS III-Worst OFF was inversely correlated with log-4-HNE levels (p = 0.002).This association remained significant after multivariate analysis and correction for multiple testing. CONCLUSIONS: Our results strongly support an association between 4-HNE levels and the progression of motor disability in advanced PD. They also provide multiple lines of evidence favoring a role for ferroptosis in PD progression. Subject to further validation, they could therefore be used to select and stratify patients for future clinical trials. TRIAL REGISTRATION: Cohort registered with ClinicalTrials.gov: NCT02360683, on January 2015.

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Journal
Neurobiology of Disease
Published
2026-04-24
DOI
https://doi.org/10.1016/j.nbd.2026.107414
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
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article

Blood-based biomarkers of ferroptosis in Parkinson's disease

Julien Labreuche, Anne‐Sophie Rolland, Vincent Huin, Élodie Hainque et al.
Neurobiology of Disease
Ferroptosis and cancer prognosis
article

Blood-based biomarkers of ferroptosis in Parkinson's disease

Julien Labreuche, Anne‐Sophie Rolland, Vincent Huin, Élodie Hainque, David Devos, Nicolas Beauval, Mary Dutheil, Isabelle Bénatru, Émeline Cailliau, David Maltête, Guillaume Garçon, David Blum, Caroline Giordana, Clément Poupelin, Stéphane Thobois, Ophélie Simonin, Alexandre Eusebio, Melissa Tir, Christine Brefel-Courbon, Lucie Hopes, Ana Marques, Jean-Christophe Corvol, Caroline Moreau, Olivier Rascol, Jean-Philippe Brandel, Béchir Jarraya
article en

Abstract

BACKGROUND: As Parkinson's disease progresses, patients require second-line treatments such as subthalamic stimulation, the benefits of which may be diminished by the onset of non-dopaminergic axial motor and cognitive disorders. This study aimed to identify blood biomarkers of ferroptosis for predicting the progression of Parkinson's disease at the stage of L-DOPA-related complications. METHODS: We analyzed 598 blood samples from patients with PD enrolled in the French multicentric PREDISTIM study. Neurofilament light chain, 4-hydroxy-2-nonenal, glutathione peroxidase activity, ferritin, alpha-synuclein and selenium levels were determined by electrochemiluminescence, ELISA or inductively coupled plasma mass spectrometry. We assessed three single-nucleotide polymorphisms in ACSL4 and GPX4 genes, two key players in ferroptosis. Overall clinical outcomes were evaluated at baseline and one-year post-surgery. RESULTS: ), selenium concentration (p = 0.033) and the rs7887981 in the ACSL4 gene (p = 0.033). Milder cognitive problems were correlated with the rs139736475 in ACSL4 (p = 0.028). One-year post-surgery, change in UPDRS III-Worst OFF was inversely correlated with log-4-HNE levels (p = 0.002).This association remained significant after multivariate analysis and correction for multiple testing. CONCLUSIONS: Our results strongly support an association between 4-HNE levels and the progression of motor disability in advanced PD. They also provide multiple lines of evidence favoring a role for ferroptosis in PD progression. Subject to further validation, they could therefore be used to select and stratify patients for future clinical trials. TRIAL REGISTRATION: Cohort registered with ClinicalTrials.gov: NCT02360683, on January 2015.

Neurobiology of DiseaseVol. 224
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université de Versailles Saint-Quentin-en-Yvelines (FR), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Institut Pasteur de Lille (FR), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nice (FR), Université de Poitiers (FR), Sorbonne Université (FR), Assistance Publique Hôpitaux de Marseille (FR), Différenciation et Communication Neuronale et Neuroendocrine (FR), Centre de Recherche en Neurosciences de Lyon (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), University of Clermont Auvergne (FR), Hôpital Pierre Wertheimer (FR), Fondation Ophtalmologique Adolphe de Rothschild (FR), CEA Paris-Saclay (FR), Institut de Neurosciences de la Timone (FR), Institut du Cerveau (FR), Hôpital de la Timone (FR), Université de Picardie Jules Verne (FR), Université de Rouen Normandie (FR)
Université de Lille, Association France Parkinson, Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, Centre hospitalier régional universitaire de Lille
Good health and well-being
Openalex Percentile: Top 18%
Ferroptosis and cancer prognosis
DOIOpen Access PDFOpenAlex
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