TAT-PPA1 protects against oxidative stress-induced loss of dopaminergic neurons

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.