Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson\u2019s Disease Mice Model Revealed by Transcriptome

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Parkinson’s disease (PD) is a neurodegenerative disease caused by a variety of unclear complex pathogenic factors. The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced progressive PD mice is a well-recognized classic model for studying PD, but the molecular toxicology of this model is still unclear. Here, for the first time, we report gradual neurodegenerative processes in MPTP/p-induced progressive PD mice model using RNA-seq. Transcriptional responses are orchestrated to regulate the expression of many genes in substantia nigra, such as Ntf3, Pitx3, Th, and Drd2, leading to the degeneration of dopaminergic neurons at last. We proposed that the established model could be divided into three phases based on their molecular toxicological features: “the stress response phase” which maintained the microenvironment homeostasis, “the pre-neurodegenerative phase” which demonstrated observed MPTP/p cytotoxicity and gradual degeneration of dopaminergic neurons, and “the neurodegenerative phase” which reflected distinct damage and dopaminergic neuron apoptotic process. Glia cells exhibited a certain protective effect on dopaminergic neurons in 3rd and 6th MPTP/p-induced cytotoxicity. But in 10th MPTP/p injection, glia cells play a promoting role in PD and tissue damages caused by oxidative stress. This study also indicated that the substantia nigra of PD mice showed unique patterns of changes at each stage. Moreover, neurotrophic signaling pathway, ECM-receptor interaction, oxidative phosphorylation, apoptosis and necroptosis were enriched at 3rd and 6th MPTP/p injection, which might be associated with the PD progress. This study provided an extensive data set of molecular toxicology for elucidating of PD progression and offered comprehensive theoretical knowledge for the development of new therapy.