Dopaminergic neuron-specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model
| Autor: | Nigel H. Greig, Emily Filichia, Austin Barnett, Brandon Davis, Barry J. Hoffer, Yung Hsiao Chiang, Yu Luo, Xin Qi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Dopamine Substantia nigra Striatum Biology Biochemistry Neuroprotection Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound medicine Animals Neurotoxin Mice Knockout Dopamine Plasma Membrane Transport Proteins Dopaminergic Neurons MPTP Dopaminergic Parkinson Disease Genes p53 medicine.disease Corpus Striatum Cell biology Astrogliosis Substantia Nigra Disease Models Animal Neuroprotective Agents 030104 developmental biology Gene Expression Regulation nervous system chemistry Neuroscience medicine.drug |
| Zdroj: | Journal of Neurochemistry. 138:746-757 |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.13706 |
| Popis: | p53, a stress response gene, is involved in diverse cell death pathways and its activation has been implicated in the pathogenesis of Parkinson's disease (PD). However, whether the neuronal p53 protein plays a direct role in regulating dopaminergic (DA) neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 knock-out (KO) mice, we examined the effect of DA specific p53 gene deletion in DAT-p53KO mice. These DAT-p53KO mice did not exhibit apparent changes in the general structure and neuronal density of DA neurons during late development and in aging. However, in DA-p53KO mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that the induction of Bax and p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein levels by MPTP were diminished in both striatum and substantia nigra of these mice. Notably, deletion of the p53 gene in DA neurons significantly reduced dopaminergic neuronal loss in substantia nigra, dopaminergic neuronal terminal loss at striatum and, additionally, decreased motor deficits in mice challenged with MPTP. In contrast, there was no difference in astrogliosis between WT and DAT-p53KO mice in response to MPTP treatment. These findings demonstrate a specific contribution of p53 activation in DA neuronal cell death by MPTP challenge. Our results further support the role of programmed cell death mediated by p53 in this animal model of PD and identify Bax, BAD and PUMA genes as downstream targets of p53 in modulating DA neuronal death in the in vivo MPTP-induced PD model. We deleted p53 gene in dopaminergic neurons in late developmental stages and found that DA specific p53 deletion is protective in acute MPTP animal model possibly through blocking MPTP-induced BAX and PUMA up-regulation. Astrocyte activation measured by GFAP positive cells and GFAP gene up-regulation in the striatum shows no difference between wt and DA-p53 ko mice. |
| Databáze: | OpenAIRE |
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