Olfactory deficits in mice overexpressing human wildtype alpha-synuclein.
Olfactory deficits in mice overexpressing human wildtype alpha-synuclein.
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DOI：
10.1111/j.1460-9568.2008.06346.x
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Chesselet MF
中科院分区：
文献类型：
--
作者：
Fleming SM;Tetreault NA;Mulligan CK;Hutson CB;Masliah E;Chesselet MF
α-突触核蛋白在中枢和周围神经系统神经元中的积累是散发性帕金森病（PD）的一个标志，α-突触核蛋白水平升高的突变可导致家族性帕金森病。在Thy1启动子（Thy1- asyn）下过表达α-突触核蛋白的转基因小鼠在整个大脑中具有高水平的α-突触核蛋白表达，但在8个月的时间内没有黑质纹状体多巴胺神经元的损失，这表明它们可能有助于模拟PD的临床前阶段。嗅觉功能障碍通常比帕金森病的主要运动症状早几年出现，包括气味检测、辨别和识别的缺陷。在本研究中，我们测量了3个月和9个月大的雄性Thy1-aSyn小鼠的嗅觉功能，采用了基于潜伏期的埋藏颗粒测试来发现暴露或隐藏的气味，基于暴露于自我和非自我气味的块测试，以及基于暴露于非社会气味的习惯化/非习惯化测试。在另一组小鼠中，评估嗅球中α-突触核蛋白的免疫反应性。与野生型小鼠相比，Thy1-aSyn小鼠仍能识别和适应气味，但在三个测试范式中均表现出嗅觉障碍。Thy1-aSyn小鼠也在嗅球中发现了蛋白酶k抗性α-突触核蛋白包涵体。这些数据表明，α-突触核蛋白的过表达足以导致小鼠嗅觉缺陷，与PD患者相似。此外，埋藏颗粒和阻断试验为检测50%的药物效果提供了足够的功率，表明它们对测试新型神经保护疗法的有用性。
Accumulation of α-synuclein in neurons of the central and peripheral nervous system is a hallmark of sporadic Parkinson’s disease (PD) and mutations that increase α-synuclein levels cause familial PD. Transgenic mice overexpressing α-synuclein under the Thy1 promoter (Thy1-aSyn) have high levels of α-synuclein expression throughout the brain but no loss of nigrostriatal dopamine neurons up to 8 months, suggesting that they may be useful to model pre-clinical stages of PD. Olfactory dysfunction often precedes the onset of the cardinal motor symptoms of PD by several years and includes deficits in odor detection, discrimination and identification. In the present study, we measured olfactory function in 3- and 9-month-old male Thy1-aSyn mice with a buried pellet test based on latency to find an exposed or hidden odorant, a block test based on exposure to self and non-self odors, and a habituation/dishabituation test based on exposure to non-social odors. In a separate group of mice, α-synuclein immunoreactivity was assessed in the olfactory bulb. Compared with wildtype littermates, Thy1-aSyn mice could still detect and habituate to odors but showed olfactory impairments in aspects of all three testing paradigms. Thy1-aSyn mice also displayed proteinase K-resistant α-synuclein inclusions throughout the olfactory bulb. These data indicate that overexpression of α-synuclein is sufficient to cause olfactory deficits in mice similar to that observed in patients with PD. Furthermore, the buried pellet and block tests provided sufficient power for the detection of a 50% drug effect, indicating their usefulness for testing novel neuroprotective therapies.
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影响因子：
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