TIGAR plays neuroprotective roles in MPP+/MPTP-induced Parkinson's disease by alleviating ferroptosis.

Parkinson's disease (PD) is a common neurodegenerative disorder worldwide, characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and is associated with iron dyshomeostasis. Ferroptosis, a form of programmed cell death, involves iron-dependent lipid peroxidation and serves as a significant regulatory mechanism in PD. This study identified Tp53-induced glycolysis and apoptosis regulator (TIGAR) as a potential regulator of ferroptosis resistance in PD development. In this study, we demonstrated that in HT22 cells, 1-methyl-4-phenylpyridinium (MPP+) increased lipid peroxidation levels and reduced cell viability. These effects were reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). MPP+ also induced elevated intracellular iron ion deposition, reactive oxygen species (ROS), and the lipid peroxidation product malondialdehyde (MDA). Meanwhile, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly decreased glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, glutathione peroxidase (GPX) activity, and TIGAR expression, all of which were reversible with TIGAR overexpression. In an MPTP-induced in vivo PD model, TIGAR overexpression markedly increased DA neurons and reduced iron deposition. To summarize, TIGAR enhances intracellular NADPH production via the promotion of the pentose phosphate pathway (PPP), reduces intracellular glutathione disulfide (GSSG) to GSH, boosts GPX activity, and inhibits ferroptosis, thus providing neuronal protection.