The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease
The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease
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DOI：
10.1073/pnas.0611671104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Hunot, Stephane
中科院分区：
文献类型：
--
作者：
Hoeglinger, Guenter U.;Breunig, Joshua J.;Hunot, Stephane
帕金森病（PD）患者黑质多巴胺能神经元（DN）变性的机制尚未完全清楚。在这里，我们表明，在死后的人体组织，这些神经元异常表达有丝分裂相关蛋白，包括E2 F-1转录因子，并出现复制其核DNA。我们进一步证明，多巴胺能神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶注射到小鼠和应用其活性代谢产物1-甲基-4-苯基吡啶到中脑文化激活视网膜母细胞瘤-E2 F通路在有丝分裂后的DN。我们还发现，细胞死亡，而不是有丝分裂后毒素诱导的DNA复制，确定在DNs的BrdU掺入。此外，阻断E2 F-1转录保护培养的DNs免受1-甲基-4-苯基吡啶的毒性。最后，E2 F-1缺陷型小鼠对1-甲基-4-苯基-1，2，3，6-四氢吡啶诱导的多巴胺能细胞死亡的抵抗力显著高于其野生型同窝小鼠。总之，BrdU掺入成熟神经元和新生神经元缺乏证据反对神经元营业额在正常条件下或在黑质的病理状态。相反，我们的研究结果表明，有丝分裂样信号在PD患者的成熟DN中被激活，并在疾病的实验模型中介导神经元死亡。因此，抑制有丝分裂样信号可能为PD的神经保护提供策略。
The mechanisms leading to degeneration of dopaminergic neurons (DNs) in the substantial nigra of patients with Parkinson's disease (PD) are not completely understood. Here, we show, in the postmortem human tissue, that these neurons aberrantly express mitosis-associated proteins, including the E2F-1 transcription factor, and appear to duplicate their nuclear DNA. We further demonstrate that the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injected into mice and application of its active metabolite 1-methyl-4-phenylpyridinium to mesencephalic cultures activate the retinoblastoma-E2F pathway in postmitotic DNs. We also find that cell death rather than mitotic division followed the toxin-induced replication of DNA, as determined by BrdU incorporation in DNs. In addition, blocking E2F-1 transcription protected cultured DNs against 1-methyl-4-phenylpyridinium toxicity. Finally, E2F-1-deficient mice were significantly more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic cell death than their wild-type littermates. Altogether, BrdU incorporation in mature neurons and lack of evidence for newborn neurons argue against neuronal turnover in normal conditions or during pathological states in the substantia nigra. Instead, our results demonstrate that mitosis-like signals are activated in mature DNs in patients with PD and mediate neuronal death in experimental models of the disease. Inhibition of mitosis-like signals may therefore provide strategies for neuroprotection in PD.