Gordana Velikić, Gordana Šupić, Dušica Marić, Dušica Marić, Miljan Puletić, Maja Ovčak Kos, Danilo Vojvodić, D Marić, D Marić
Neurodegenerative diseases are widely viewed as brain-centric disorders defined by neuronal loss and protein aggregation. Yet decades of failed disease-modifying trials and mounting evidence of early peripheral symptoms suggest that this view is incomplete. This perspective review uses α-synucleinopathies as an illustrative example to outline how organ-brain axes, exosomal signaling, and strain competition shape disease trajectory, proposing a new clinical model: precision ecosystem medicine. This paradigm shift conceptualizes neurodegeneration as the late-stage manifestation of systemic ecosystem collapse: a progressive breakdown in inter-organ homeostasis driven by microbial imbalance, immune dysfunction, viral reactivation, co-infections, environmental stressors, and toxicant accumulation, when protective systems become saturated. Misfolded proteins such as α-synuclein act as prion-like mediators of this collapse, with distinct conformational "strains" emerging in different organ environments and may propagate to the brain via exosomes and neural pathways. Analyses suggest that understanding these systemic interactions could reveal new therapeutic windows before significant neurodegeneration occurs. This integrative approach establishes a conceptual foundation for regenerative therapies that address the complexity of neurodegenerative diseases beyond symptom management, offering promising directions for revolutionizing patient care with precise, multi-targeted strategies. Reframing neurodegeneration as a multi-organ, ecosystem-level disorder opens new paths for prevention, prediction, and potentially disease-modifying therapies, laying the theoretical foundation for a field of precision ecosystem medicine.