Beyond Symptom Control - Mechanistic Lessons from Failed and Emerging Disease-Modifying Therapies in Parkinson’s Disease

Parkinson’s disease (PD) remains the second most common neurodegenerative disorder worldwide, yet despite decades of mechanistic insight, every clinical trial of a disease-modifying therapy (DMT) to date has failed to deliver unequivocal evidence of slowed neurodegeneration. Recent high-profile negative results — including trials of NLY01 (a GLP-1 receptor agonist targeting microglial activation) and deferiprone (an iron chelator targeting nigral iron accumulation and ferroptotic vulnerability) — have prompted a critical re-examination of the preclinical models, target validation strategies, and molecular hypotheses that underpin the DMT pipeline.These setbacks raise fundamental mechanistic questions. Did the preclinical models faithfully capture the molecular pathology being targeted? Were biomarkers of target engagement sufficient to confirm that the drug reached and modulated the intended pathway? Do negative outcomes reflect a flawed mechanistic premise, the wrong patient population, the wrong disease stage, or limitations in our understanding of α-synuclein propagation, mitochondrial dysfunction, neuroinflammation, lysosomal–autophagic failure, and iron-mediated oxidative injury in dopaminergic neurons?This Research Topic invites contributions that interrogate the molecular and cellular mechanisms underlying current and emerging DMT strategies for PD. We welcome work using in vivo preclinical models, patient-derived cell systems (iPSC-derived dopaminergic neurons, midbrain organoids), and mechanistic biomarker studies to refine our understanding of why specific therapeutic hypotheses succeed, fail, or require reformulation. Submissions that bridge preclinical mechanistic insight with translational endpoints — without devolving into purely clinical reporting — are particularly encouraged.We welcome submissions exploring, but not limited to:o Mechanistic re-evaluation of failed or emerging DMT trials (NLY01, deferiprone, isradipine, prasinezumab, cinpanemab, exenatide) and what their outcomes reveal about underlying PD pathologyo Preclinical model fidelity: how MPTP, 6-OHDA, α-synuclein PFF, AAV-α-synuclein, LRRK2, GBA, and PINK1/Parkin models reproduce — or fail to reproduce — the molecular substrates targeted by DMTso α-Synuclein-targeted approaches: aggregation inhibitors, immunotherapies, and antisense oligonucleotideso Iron homeostasis, ferroptosis, and oxidative stress in nigral dopaminergic vulnerabilityo Neuroinflammation and microglial activation as DMT targets, including GLP-1, NLRP3, and TLR pathway modulationo Mitochondrial quality control, PINK1/Parkin signalling, and mitophagy as therapeutic leverso Lysosomal–autophagic dysfunction and GBA-related glucocerebrosidase therapieso Genetic stratification (LRRK2, GBA, SNCA, PRKN) and its implications for mechanism-driven trial designo Mechanistic biomarkers of target engagement and progression: α-synuclein seed amplification assays, neurofilament light, and neuroimaging correlateso Patient-derived iPSC and organoid platforms for predicting DMT efficacy and identifying responder subgroupsWe invite original research, reviews, methodological papers, and perspectives that strengthen the mechanistic foundation of PD disease-modifying therapy development. Contributions using in vivo preclinical models or patient-derived cell systems, identifying novel molecular targets, or clarifying why specific therapeutic hypotheses have or have not translated to the clinic are particularly welcome.By consolidating mechanistic insight from across the DMT pipeline — successes, failures, and emerging strategies alike — this Research Topic aims to sharpen target validation, improve preclinical-to-clinical translation, and accelerate the development of therapies that meaningfully alter the course of Parkinson’s disease. Topic editors: Thomas Mueller, Kah-Leong Lim Source: https://www.frontiersin.org/research-topics/84969/beyond-symptom-control---mechanistic-lessons-from-failed-and-emerging-disease-modifying-therapies-in-parkinsons-disease