Gilman Charles P, Chan Sic L, Guo Zhihong, Zhu Xiaoxiang, Greig Nigel, Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Neuromolecular Med. 2003;3(3):159-72. doi: 10.1385/NMM:3:3:159.
A form of programmed cell-death called apoptosis occurs in neurons during development of the nervous system, and may also occur in a variety of neuropathological conditions. Here we present evidence obtained in studies of adult mice and neuronal cell cultures showing that p53 protein is present in synapses where its level and amount of phosphorylation are increased following exposure of the cells to the DNA-damaging agent etoposide. We also show that levels of active p53 increase in isolated cortical synaptosomes exposed to oxidative and excitotoxic insults. Increased levels of p53 also precede loss of synapsin I immunoreactive terminals in cultured hippocampal neurons exposed to etoposide. Synaptosomes from p53-deficient mice exhibit increased resistance to oxidative and excitotoxic insults as indicated by stabilization of mitochondrial membrane potential and decreased production of reactive oxygen species. Finally, we show that a synthetic inhibitor of p53 (PFT-alpha) protects synaptosomes from wild-type mice against oxidative and excitotoxic injuries, and preserves presynaptic terminals in cultured hippocampal neurons exposed to etoposide. Collectively, these findings provide the first evidence for a local transcription-independent action of p53 in synapses, and suggest that such a local action of p53 may contribute to the dysfunction and degeneration of synapses that occurs in various neurodegenerative disorders.
一种名为凋亡的程序性细胞死亡形式在神经系统发育过程中发生于神经元，并且也可能发生在多种神经病理状况下。在此，我们展示在成年小鼠和神经元细胞培养物研究中获得的证据，表明p53蛋白存在于突触中，在细胞暴露于DNA损伤剂依托泊苷后，其水平和磷酸化量会增加。我们还表明，在暴露于氧化和兴奋毒性损伤的分离皮质突触体中，活性p53水平会升高。在暴露于依托泊苷的培养海马神经元中，p53水平升高也先于突触素I免疫反应性终末的丧失。来自p53基因缺陷小鼠的突触体表现出对氧化和兴奋毒性损伤的抗性增加，这表现为线粒体膜电位的稳定和活性氧产生的减少。最后，我们表明p53的一种合成抑制剂（PFT-α）可保护野生型小鼠的突触体免受氧化和兴奋毒性损伤，并在暴露于依托泊苷的培养海马神经元中保留突触前终末。总体而言，这些发现为p53在突触中的局部非转录依赖性作用提供了首个证据，并表明p53的这种局部作用可能导致各种神经退行性疾病中发生的突触功能障碍和退化。
