A dual-hit animal model for age-related parkinsonism
A dual-hit animal model for age-related parkinsonism
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DOI：
10.1016/j.pneurobio.2009.10.013
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发表时间：
2010-02-09
影响因子：
6.7
通讯作者：
Middaugh, Lawrence D.
中科院分区：
文献类型：
--
作者：
Boger, Heather A.;Granholm, Ann-Charlotte;Middaugh, Lawrence D.
帕金森病是一种神经系统疾病，困扰着越来越多的人。如果包括被称为“年龄相关性帕金森病”的更广泛的锥体外系症状，则 80 岁以上人口的发病率接近 50%。这篇综述总结了我们实验室和其他研究小组的最新研究，旨在探索年龄相关神经变性的多方面病因，特别是黑质多巴胺能神经元的变性。近年来，我们的工作重点是评估神经胶质细胞源性神经营养因子（GDNF）减少与衰老过程（内在因素）和早期神经毒素暴露（外在因素）对多巴胺（DA）系统及其介导的行为的潜在相互作用影响。指导本研究的指导性假设是，这两个因素的结合会加剧老化期间发生的 DA 发射器系统功能的衰退。获得的结果与利用 DA 作为递质和运动功能的神经元功能和结构的衰老相关衰退相一致，并通过确定 Gdnf 的遗传减少加剧了这些衰老相关的变化来扩展了知识。因此，GDNF 的减少似乎增加了 DA 神经元对与衰老过程相关的许多不同挑战的脆弱性。甲基苯丙胺对年轻 Gdnf(+/-) 小鼠影响的评估表明，GDNF 可用性的降低增加了 DA 系统对这种成熟神经毒素的脆弱性。本综述中讨论的工作与早期的工作一致，证明了 GDNF 对于维持 DA 神经元的重要性，并且还提供了进行性 DA 变性和运动功能障碍的新模型。 (C) 2009 Elsevier Ltd. 保留所有权利。
Parkinson's disease is a neurological disorder which afflicts an increasing number of individuals. If the wider complex of extrapyramidal symptoms referred to as "age-related parkinsonism" is included, the incidence is near 50% of the population above 80 years of age. This review summarizes recent studies from our laboratories as well as other research groups in the quest to explore the multi-faceted etiology of age-related neurodegeneration, in general, and degeneration of the substantia nigra dopaminergic neurons, in particular. Our work during recent years has focused on assessment of potential interactive effects of a reduction in glial cell line-derived neurotrophic factor (GDNF) and the aging process (intrinsic factors) and early neurotoxin exposure (an extrinsic factor) on dopamine (DA) systems and the behaviors they mediate. The guiding hypothesis directing the research to be described was that a combination of the two factors would exacerbate the decline in the DA transmitter system function that occurs during aging. The results obtained were consistent with the well-established aging-related decline in function and structure of neurons utilizing DA as a transmitter and motor function, and extended knowledge by establishing that the genetic reduction of Gdnf exacerbated these aging related changes. Thus, GDNF reduction appears to increase the vulnerability of the DA neurons to the many different challenges associated with the aging process. Assessment of methamphetamine effects on young Gdnf(+/-) mice indicated that reduced GDNF availability increased the vulnerability of DA systems to this well-established neurotoxin. The work discussed in this review is consistent with earlier work demonstrating the importance of GDNF for maintenance of DA neurons and also provides a novel model for progressive DA degeneration and motor dysfunction. (C) 2009 Elsevier Ltd. All rights reserved.