Perez Francisco A, Curtis Wendy R, Palmiter Richard D
Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195, USA.
BMC Neurosci. 2005 Dec 24;6:71. doi: 10.1186/1471-2202-6-71.
Autosomal recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene which encodes an E3 ubiquitin-protein ligase. Parkin is thought to be critical for protecting dopaminergic neurons from toxic insults by targeting misfolded or oxidatively damaged proteins for proteasomal degradation. Surprisingly, mice with targeted deletions of parkin do not recapitulate robust behavioral or pathological signs of parkinsonism. Since Parkin is thought to protect against neurotoxic insults, we hypothesized that the reason Parkin-deficient mice do not develop parkinsonism is because they are not exposed to appropriate environmental triggers. To test this possibility, we challenged Parkin-deficient mice with neurotoxic regimens of either methamphetamine (METH) or 6-hydroxydopamine (6-OHDA). Because Parkin function has been linked to many of the pathways involved in METH and 6-OHDA toxicity, we predicted that Parkin-deficient mice would be more sensitive to the neurotoxic effects of these agents.
We found no signs consistent with oxidative stress, ubiquitin dysfunction, or degeneration of striatal dopamine neuron terminals in aged Parkin-deficient mice. Moreover, results from behavioral, neurochemical, and immunoblot analyses indicate that Parkin-deficient mice are not more sensitive to dopaminergic neurotoxicity following treatment with METH or 6-OHDA.
Our results suggest that the absence of a robust parkinsonian phenotype in Parkin-deficient mice is not due to the lack of exposure to environmental triggers with mechanisms of action similar to METH or 6-OHDA. Nevertheless, Parkin-deficient mice could be more sensitive to other neurotoxins, such as rotenone or MPTP, which have different mechanisms of action; therefore, identifying conditions that precipitate parkinsonism specifically in Parkin-deficient mice would increase the utility of this model and could provide insight into the mechanism of AR-JP. Alternatively, it remains possible that the absence of parkinsonism in Parkin-deficient mice could reflect fundamental differences between the function of human and mouse Parkin, or the existence of a redundant E3 ubiquitin-protein ligase in mouse that is not found in humans. Therefore, additional studies are necessary to understand why Parkin-deficient mice do not display robust signs of parkinsonism.
常染色体隐性青少年帕金森病（AR-JP）由编码E3泛素蛋白连接酶的parkin基因突变引起。Parkin被认为对于通过将错误折叠或氧化损伤的蛋白质靶向蛋白酶体降解来保护多巴胺能神经元免受毒性损伤至关重要。令人惊讶的是，parkin基因靶向缺失的小鼠并未重现帕金森病典型的行为或病理体征。由于Parkin被认为可抵御神经毒性损伤，我们推测Parkin基因缺陷小鼠未发生帕金森病的原因是它们未接触到合适的环境触发因素。为验证这一可能性，我们用甲基苯丙胺（METH）或6-羟基多巴胺（6-OHDA）的神经毒性方案对Parkin基因缺陷小鼠进行了挑战。由于Parkin的功能与许多参与METH和6-OHDA毒性的途径相关，我们预测Parkin基因缺陷小鼠对这些药物的神经毒性作用会更敏感。
我们在老年Parkin基因缺陷小鼠中未发现与氧化应激、泛素功能障碍或纹状体多巴胺神经元终末变性一致的体征。此外，行为学、神经化学和免疫印迹分析结果表明，Parkin基因缺陷小鼠在接受METH或6-OHDA治疗后对多巴胺能神经毒性并不更敏感。
我们的结果表明，Parkin基因缺陷小鼠缺乏典型帕金森病表型并非由于未接触到作用机制与METH或6-OHDA相似的环境触发因素。然而，Parkin基因缺陷小鼠可能对其他具有不同作用机制的神经毒素（如鱼藤酮或MPTP）更敏感；因此，确定能使Parkin基因缺陷小鼠特异性发生帕金森病的条件将增加该模型的实用性，并可能为AR-JP的发病机制提供深入了解。或者，Parkin基因缺陷小鼠未发生帕金森病仍有可能反映了人类和小鼠Parkin功能的根本差异，或小鼠中存在人类所没有的冗余E3泛素蛋白连接酶。因此，有必要进行更多研究以了解Parkin基因缺陷小鼠为何未表现出典型的帕金森病体征。
