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

Autor: Zhuo Meng, Tao Zhang, Xiaosong Gu, Xiaodi Li, Shiyan Ding, Weiwei Yang, Lian Xu, Yu Zhang, Jian Yang, Weixiao Huang, Wenwen Hao
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Parkinson's disease
MPTP/p
Tyrosine 3-Monooxygenase
Necroptosis
Neuroscience (miscellaneous)
Substantia nigra
medicine.disease_cause
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
medicine
Animals
Neurodegeneration
biology
Behavior
Animal
Probenecid
MPTP
Dopaminergic
Molecular toxicology
MPTP Poisoning
Reproducibility of Results
RNA sequencing
Parkinson Disease
medicine.disease
Cell biology
Mice
Inbred C57BL
Substantia Nigra
Disease Models
Animal
030104 developmental biology
Neurology
chemistry
nervous system
Gene Expression Regulation
1-Methyl-4-phenyl-1
2
3
6-tetrahydropyridine
Nerve Degeneration
biology.protein
Parkinson’s disease
Transcriptome
030217 neurology & neurosurgery
Oxidative stress
Neurotrophin
Zdroj: Molecular Neurobiology
ISSN: 1559-1182
0893-7648
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s12035-020-02128-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
Externí odkaz: