Lack of p53 delays apoptosis, but increases ubiquitinated inclusions, in proteasomal inhibitor-treated cultured cortical neurons
Lack of p53 delays apoptosis, but increases ubiquitinated inclusions, in proteasomal inhibitor-treated cultured cortical neurons
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DOI：
10.1016/s1044-7431(03)00201-x
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Stefanis, L
中科院分区：
文献类型：
--
作者：
Dietrich, P;Rideout, HJ;Stefanis, L
蛋白酶体功能障碍可能导致神经退行性疾病;然而，其对原代神经元的影响在很大程度上是未知的。我们以前曾报道，药理学蛋白酶体抑制导致原代大鼠皮层神经元细胞凋亡和细胞质泛素化包涵体。在细胞系中，转录因子p53受蛋白酶体调节，在某些情况下，它介导蛋白酶体抑制后的死亡。然而，目前还不清楚初级神经元中是否存在这种情况。在这里，我们显示在蛋白酶体转运蛋白处理的皮层神经元p53水平的早期增加，伴随着核转位。在稍后的时间点，发现p53被隔离在泛素化的包涵体中。与对照组相比，p53缺陷型小鼠神经元表现出延迟的凋亡，但夹杂物的数量增加，可能继发于增强的生存。我们的结论是，p53蛋白酶体抑制诱导的皮质神经元凋亡中发挥作用，尽管事实上，它本地化的夹杂物，它是没有必要的形成。(C)2003年爱思唯尔公司All rights reserved.
Proteasomal dysfunction may contribute to neurodegenerative diseases; however, its effects on primary neurons are largely unknown. We have previously reported that pharmacological proteasomal inhibition leads to apoptosis and cytoplasmic ubiquitinated inclusions in primary rat cortical neurons. In cell lines the transcription factor p53 is regulated by the proteasome and in some cases it mediates death following proteasomal inhibition. It is unclear, however, if this is the case in primary neurons. Here we show in proteasome inhibitor-treated cortical neurons an early increase of p53 levels, accompanied by nuclear translocation. At later time points p53 is found sequestered within ubiquitinated inclusions. Compared to controls, p53-deficient mouse neurons show delayed apoptosis, but increased numbers of inclusions, likely secondary to enhanced survival. We conclude that p53 plays a role in cortical neuron apoptosis induced by proteasomal inhibition and, despite the fact that it localizes to inclusions, it is not necessary for their formation. (C) 2003 Elsevier Inc. All rights reserved.