Oxidative stress and regulated cell death in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Motor deficits usually associated with PD correlate with dopaminergic axonal neurodegeneration starting at the striatum, which is then followed by dopaminergic neuronal death in the substantia nigra pars compacta (SN), with both events occurring already at the prodromal stage. We will overview the main physiological characteristics responsible for the higher susceptibility of the nigrostriatal circuit to mitochondrial dysfunction and oxidative stress, as hinted by the acting mechanisms of the PD-causing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Then, we will present multiple lines of evidence linking several cell death mechanisms involving mitochondria and production of reactive oxygen species to neuronal loss in PD, namely intrinsic and extrinsic apoptosis, necroptosis, ferroptosis, parthanatos and mitochondrial permeability transition-driven necrosis. We will focus on gathered data from postmortem PD samples and relevant in vivo models, especially MPTP-based models.