Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease.
Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease.
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DOI：
10.1371/journal.pone.0031522
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Strong R
中科院分区：
文献类型：
--
作者：
Wey MC;Fernandez E;Martinez PA;Sullivan P;Goldstein DS;Strong R
先前的研究报告称，帕金森病 (PD) 患者大脑中的生物醛水平升高。在大脑中，醛类主要通过乙醛脱氢酶 (ALDH) 解毒。据报道，死于 PD 的患者大脑中幸存的中脑多巴胺神经元中 ALDH1 表达降低。此外，复合物 I 活性受损（在 PD 中已得到充分证明）会降低多种 ALDH 异构体催化去除生物醛所需的 NAD+ 辅因子的可用性。我们推测，由于暴露于环境毒素和/或 ALDH 表达减少而导致的多种乙醛脱氢酶功能的长期下降，在 PD 的病理生理学中发挥着重要作用。为了解决这个假设，我们生成了 Aldh1a1 和 Aldh2 缺失的小鼠，这两种亚型已知在黑质多巴胺神经元中表达。 Aldh1a1−/−×Aldh2−/− 小鼠在通过步态分析和加速旋转棒上的表现评估的运动表现方面表现出年龄依赖性缺陷。腹腔注射左旋多巴加苄丝肼可缓解运动能力的缺陷。我们观察到 Aldh1a1−/−×Aldh2−/− 小鼠黑质中酪氨酸羟化酶 (TH) 免疫反应性神经元显着减少，纹状体中多巴胺和代谢物减少。我们还观察到据报道具有神经毒性的生物醛显着增加，包括 4-羟基壬烯醛 (4-HNE) 和多巴胺代谢的醛中间体 3,4-二羟基苯乙醛 (DOPAL)。这些结果支持生物醛解毒受损可能在 PD 病理生理学中很重要的假设，并表明 Aldh1a1−/−×Aldh2−/− 小鼠可能是有用的 PD 动物模型。
Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD+ co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1−/−×Aldh2−/− mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1−/−×Aldh2−/− mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1−/−×Aldh2−/− mice may be a useful animal model of PD.
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影响因子：
4.4
作者：
Chen J;Wang L;Chen Y;Sternberg P;Cai J
通讯作者：
Cai J
影响因子：
3
作者：
Hao, Pan-Pan;Chen, Yu-Guo;Zhang, Yun
通讯作者：
Zhang, Yun
影响因子：
2.6
作者：
CANAVAN, AGM;PASSINGHAM, RE;POLKEY, CE
通讯作者：
POLKEY, CE
影响因子：
6.1
作者：
Galter, D;Buervenich, S;Olson, L
通讯作者：
Olson, L
DOI：
10.1111/j.1530-0277.2006.00200.x
发表时间：
2006-10-01
影响因子：
3.2
作者：
Fernandez, Elizabeth;Koek, Wouter;Strong, Randy
通讯作者：
Strong, Randy