Beyond dopamine: the role of non-dopaminergic systems in Parkinson’s disease

Abstract Parkinson’s disease (PD) has long been considered a disorder of dopamine depletion. However, dopaminergic dysfunction alone cannot explain its clinical complexity. Emerging evidence implicates non-dopaminergic systems degeneration/dysregulation‌ as critical contributors to PD’s multifaceted pathology. Integrating these systems into a framework of network dysfunction, this review synthesizes current knowledge on the role of non-dopaminergic systems in PD pathogenesis, symptomatology, and therapeutic advancement, advocating for a paradigm shift toward multisystem-targeted therapies.