Quantitative Phosphoproteomic Analysis in Alpha-Synuclein Transgenic Mice Reveals the Involvement of Aberrant p25/Cdk5 Signaling in Early-stage Parkinson's Disease
Autor: | Jingyu Chen, Ming Li, Tongxia Li, Qiaofeng Zhang, Feng He, Jie Ming, Hongwei Cai, Zhang Pei, Bo Tian, Guangjian Qi, Qian Zhang |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Genetically modified mouse Male Proteomics Transgene Down-Regulation Substantia nigra Mice Transgenic Biology Substrate Specificity 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Animals Humans Protein phosphorylation Phosphorylation Databases Protein Alpha-synuclein Pars compacta Cyclin-dependent kinase 5 Cyclin-Dependent Kinase 5 Parkinson Disease Cell Biology General Medicine Phosphoproteins nervous system diseases Cell biology Up-Regulation Mice Inbred C57BL Disease Models Animal 030104 developmental biology Gene Ontology nervous system chemistry alpha-Synuclein 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Cellular and molecular neurobiology. 40(6) |
ISSN: | 1573-6830 |
Popis: | A30P and A53T mutations in the gene encoding alpha-synuclein-a presynaptic protein-are the most frequently identified genetic causes of Parkinson's disease (PD). Aberrant alpha-synuclein likely plays central roles in dopaminergic neuronal death and motor symptoms in PD. This study investigated the protein phosphorylation profile in early-stage PD through phosphoproteomic analyses of tissue samples from the substantia nigra pars compacta (SNpc) of 6-month-old alpha-synuclein transgenic mice (A30P/A53T double-mutant human alpha-synuclein; hm2α-SYN-39 strain). We identified 5351 phosphorylation sites in 2136 phosphoproteins. Of these, 357 upregulated sites in 245 proteins and 50 downregulated sites in 46 proteins were differentially phosphorylated between alpha-synuclein transgenic and wildtype mice. Bioinformatic analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and motif analyses, were used to elucidate the molecular and cellular mechanisms underlying double-mutant human alpha-synuclein overexpression. Scansite-based computational analysis and prediction of differentially quantitated phosphoproteins identified the neuronal protein cyclin-dependent kinase 5 (Cdk5) as the most significantly enriched kinase. Biochemical experiments suggested that the p25/Cdk5 pathway was activated in an MPP+-induced cell culture model and MPTP-induced mouse model. Moreover, Cdk5 could directly phosphorylate the Ank2 protein at Ser1889 in vitro. Therefore, quantitative phosphoproteomic using an alpha-synuclein transgenic mouse model offers a powerful approach for elucidating the protein phosphorylation mechanism underlying SNpc dopaminergic neuronal death in an animal model of PD. |
Databáze: | OpenAIRE |
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