Molecular crosstalk between MAPK signaling and neuroprotective pathways in Parkinson's disease: from pathogenesis to...

Mitogen-activated protein kinase (MAPK) signaling is increasingly recognized as a central regulator in the pathogenesis of Parkinson's disease (PD). PD is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), driven by a complex interplay of mitochondrial dysfunction, oxidative stress, and neuroinflammation. While basal MAPK activity is essential for neuroprotection and neuronal growth, its overactivation, specifically via the JNK and p38 cascades, accelerates neurodegeneration. This review explores the molecular landscape of MAPK signaling, detailing how its dysregulation promotes the accumulation of alpha-synuclein and the activation of microglia. Furthermore, it highlights critical crosstalk between MAPK and other vital pathways, including the inhibition of the neuroprotective PI3K/AKT and PP2A pathways and the detrimental activation of GSK-3β and PTEN signaling. Preclinical evidence strongly supports the use of MAPK inhibitors to mitigate dopaminergic neurotoxicity and reduce proinflammatory cytokine release. Despite promising results in experimental models and the development of highly selective inhibitors, clinical translation remains challenging due to potential systemic toxicities. This manuscript provides a comprehensive synthesis of mounting and mooting evidence, positioning MAPK inhibition as a potent, albeit complex, adjuvant strategy for delaying the onset and progression of PD neuropathology.