Cell Death-Osis of Dopaminergic Neurons and the Role of Iron in Parkinson's Disease

Significance: There is still no cure for neurodegenerative diseases, such as Parkinson's disease (PD). Current treatments are based on the attempt to reduce dopaminergic neuronal loss, and multidisciplinary approaches have been used to provide only a temporary symptoms' relief. In addition to the difficulties of drugs developed against PD to access the brain, the specificity of those inhibitory compounds could be a concern. This because neurons might degenerate by activating distinct signaling pathways, which are often initiated by the same stimulus. Recent Advances: Apoptosis, necroptosis, and ferroptosis were shown to significantly contribute to PD progression and, so far, are the main death programs described as capable to alter brain homeostasis. Their activation is characterized by different biochemical and morphological features, some of which might even share the same molecular players. Critical Issues: If there is a pathological need to engage, in PD, multiple death programs, sequentially or simultaneously, is not clear yet. Possibly the activation of apoptosis, necroptosis, and/or ferroptosis correlates to different PD stages and symptom severities. This would imply that the efficacy of therapeutic approaches against neuronal death might depend on the death program they target and the relevance of this death pathway on a specific PD phase. Future Directions: In this review, we describe the molecular mechanisms underlying the activation of apoptosis, necroptosis, and ferroptosis in PD. Understanding the interrelationship between different death pathways' activation in PD is of utmost importance for the development of therapeutic approaches against disease progression. Antioxid. Redox Signal. 35, 453-473.