Parkin-Mediated Protection of Dopaminergic Neurons in a Chronic MPTP-Minipump Mouse Model of Parkinson Disease
Parkin-Mediated Protection of Dopaminergic Neurons in a Chronic MPTP-Minipump Mouse Model of Parkinson Disease
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DOI：
10.1097/nen.0b013e3182269ecd
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发表时间：
2011-08
影响因子：
3.2
通讯作者：
T. Yasuda;H. Hayakawa;T. Nihira;Yong Ren;Y. Nakata;M. Nagai;N. Hattori;K. Miyake;M. Takada;T. Shimada;Y. Mizuno;H. Mochizuki
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文献类型：
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作者：
T. Yasuda;H. Hayakawa;T. Nihira;Yong Ren;Y. Nakata;M. Nagai;N. Hattori;K. Miyake;M. Takada;T. Shimada;Y. Mizuno;H. Mochizuki
泛素连接酶帕金森氏的功能缺失突变是隐性遗传早发性帕金森氏病（PD）的主要原因。由亚硝化或多巴胺相关修饰引起的帕金活性损伤也可能是散发性PD中多巴胺能（DA）神经元丢失的原因。先前的研究表明，在几种动物模型中，病毒载体介导的parkin递送可预防DA神经退行性变，但对parkin在体内的神经保护作用知之甚少。在这里，我们通过渗透小泵给药1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），研究了在改良的长期PD小鼠模型中过表达parkin的神经保护机制。重组腺相关病毒载体介导的parkin黑质内递送可预防小鼠运动缺陷和DA细胞丢失。在帕金森治疗小鼠的黑质中，ser129磷酸化-突触核蛋白免疫反应细胞增加。此外，给药帕金可减轻mptp诱导的活性磷酸化形式Akt的减少。另一方面，慢性MPTP诱导的p53上调和线粒体改变几乎没有被parkin抑制。这些结果表明，帕金的神经保护作用可能在严重帕金森病中受损。
Loss-of-function mutations in the ubiquitin ligase parkin are the major cause of recessively inherited early-onset Parkinson disease (PD). Impairment of parkin activity caused by nitrosative or dopamine-related modifications may also be responsible for the loss of dopaminergic (DA) neurons in sporadic PD. Previous studies have shown that viral vector-mediated delivery of parkin prevented DA neurodegeneration in several animal models, but little is known about theneuroprotective actions of parkin in vivo. Here, we investigated mechanisms of neuroprotection of overexpressed parkin in a modifiedlong-term mouse model of PD using osmotic minipump administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Recombinant adeno-associated viral vector-mediated intranigral delivery of parkin prevented motor deficits and DA cell loss in the mice. Ser129-phosphorylated -synuclein-immunoreactive cells were increased in the substantia nigra of parkin-treated mice. Moreover, delivery of parkin alleviated the MPTP-induced decrease of the active phosphorylated form of Akt. On the other hand, upregulation of p53 and mitochondrial alterations induced by chronic MPTP administration were barely suppressed by parkin. These results suggest that the neuroprotective actions of parkin may be impaired in severe PD.