Programmed Cell Death and Its Therapeutic Implications in Parkinson's Disease: A Review of Apoptosis, Autophagy, Ferroptosis, and Necroptosis

Abstract

ABSTRACT Parkinson's disease is a multifactorial neurodegenerative disorder characterized by progressive dopaminergic neuronal loss in the substantia nigra pars compacta and widespread α‐synuclein pathology. Despite extensive research, the precise molecular mechanisms underlying neuronal death remain incompletely defined. Emerging evidence indicates that multiple forms of programmed cell death (PCD), including apoptosis, autophagy failure, ferroptosis, and necroptosis, contribute to dopaminergic degeneration in distinct but overlapping contexts. This review synthesizes current insights from both post‐mortem human studies and experimental models to delineate the biochemical and pathological signatures of these PCD pathways in Parkinson's disease. Post‐mortem findings demonstrate heterogeneous and often coexisting PCD markers, suggesting that different neuronal subsets within the substantia nigra pars compacta may follow distinct death programs depending on their metabolic profile, iron load, and inflammatory milieu. In contrast, experimental models reveal more discrete pathway‐specific activation patterns: apoptosis predominates in acute toxin paradigms, autophagy failure in genetic models, ferroptosis in iron‐overload and oxidative stress conditions, and necroptosis in inflammation‐augmented models. The apparent discrepancies between human and experimental evidence reflect differences in temporal resolution, pathogenic drivers, and neuronal heterogeneity but together support a unified model of multifactorial, context‐dependent cell death. Finally, preclinical studies targeting these pathways, through caspase inhibition, autophagy enhancement, ferroptosis suppression, or necroptosis blockade, have provided proof‐of‐concept neuroprotection, although translation to clinical efficacy remains elusive. Understanding how these interconnected PCD pathways converge during Parkinson's disease progression is essential for developing multimodal therapeutic strategies that move beyond symptomatic relief toward accurate disease modification.

Affiliated Institutions

• Jordan University of Science and Technology JO

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