在帕金森病的1-甲基-4-苯基-1,2,3,6-四氢吡啶小鼠模型中，Bax基因敲除可预防多巴胺能神经元变性。
Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
作者信息
Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D, Korsmeyer S J, Przedborski S
机构信息
Department of Neurology, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
出版信息
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2837-42. doi: 10.1073/pnas.051633998. Epub 2001 Feb 13.
Abstract
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the pro-apoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease.
摘要
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）会损害黑质致密部（SNpc）中的多巴胺能神经元，这在帕金森病中可见。在此，我们表明促凋亡蛋白Bax在SNpc中高度表达，并且其缺失可减轻SNpc发育过程中的神经元凋亡。在成年小鼠中，给予MPTP后SNpc中Bax上调，而Bcl-2减少。这些变化与MPTP诱导的多巴胺能神经变性平行。我们还表明，缺乏Bax的突变小鼠比其野生型同窝小鼠对MPTP的抵抗力明显更强。这项研究表明，Bax在MPTP神经毒性过程中起关键作用，并表明靶向Bax可能在帕金森病治疗中提供保护作用。
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本文引用的文献
1
Naturally Occurring Cell Death during Postnatal Development of the Substantia Nigra Pars Compacta of Rat.大鼠黑质致密部出生后发育过程中的自然发生细胞死亡。
Mol Cell Neurosci. 1993 Feb;4(1):30-5. doi: 10.1006/mcne.1993.1004.
2
The parkinsonian toxin MPTP: action and mechanism.帕金森病毒素MPTP：作用与机制
Restor Neurol Neurosci. 2000;16(2):135-142.
3
The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety.帕金森病毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）：关于其效用与安全性的技术综述
J Neurochem. 2001 Mar;76(5):1265-74. doi: 10.1046/j.1471-4159.2001.00183.x.
4
BAX-dependent transport of cytochrome c reconstituted in pure liposomes.细胞色素c在纯脂质体中的BAX依赖性转运
Nat Cell Biol. 2000 Aug;2(8):553-5. doi: 10.1038/35019596.
5
Developmental cell death in dopaminergic neurons of the substantia nigra of mice.小鼠黑质多巴胺能神经元中的发育性细胞死亡。
J Comp Neurol. 2000 Aug 28;424(3):476-88. doi: 10.1002/1096-9861(20000828)424:3<476::aid-cne6>3.0.co;2-0.
6
Bax inactivation in lurcher mutants rescues cerebellar granule cells but not purkinje cells or inferior olivary neurons.在蹒跚突变体中Bax失活可挽救小脑颗粒细胞，但不能挽救浦肯野细胞或下橄榄核神经元。
J Neurosci. 2000 Jul 15;20(14):5339-45. doi: 10.1523/JNEUROSCI.20-14-05339.2000.
7
Neurodegeneration in Lurcher mice occurs via multiple cell death pathways.Lurcher小鼠的神经退行性变通过多种细胞死亡途径发生。
J Neurosci. 2000 May 15;20(10):3687-94. doi: 10.1523/JNEUROSCI.20-10-03687.2000.
8
Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease.半胱天冬酶-3：帕金森病中多巴胺能神经元凋亡性死亡的一个脆弱因素和最终效应因子。
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2875-80. doi: 10.1073/pnas.040556597.
9
Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP.帕金森毒素MPTP给药后黑质多巴胺能神经元中α-突触核蛋白上调。
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10
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Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):889-94. doi: 10.1073/pnas.97.2.889.
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