Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Neuroscience. 2011 Jan 13;172:379-86. doi: 10.1016/j.neuroscience.2010.10.072. Epub 2010 Nov 3.
Parkinson's disease (PD) involves both motor and non-motor disturbances. Non-motor features include alterations in sensory olfactory function which may constitute a viable biomarker for the disorder. It is not clear what causes olfactory dysfunction but it appears to coincide with the development of synucleopathy within the olfactory bulb (OB). Elevation in alpha-synuclein (a-syn) is indeed a risk factor for development of the sporadic disorder. The multifactorial nature of the idiopathic disease combined with variability in its presentation suggests that it is likely to be influenced by several factors and that in vivo models that explore the synergistic effect of alpha-synuclein elevation with other potential contributing factors are likely to be of importance in understanding the disease etiology. Using a dual transgenic (DTg) mouse model of dopaminergic alpha-synuclein overexpression coupled with doxycycline (Dox)-inducible glutathione (GSH) depletion in these same cells, we demonstrate an age-related loss in behavioral olfactory function coupled with a significant neurodegeneration of glomerular dopaminergic neurons. This is accompanied by increase in alpha-synuclein levels in non-dopaminergic cells in the granule cell layer (GCL). In addition, isolated olfactory bulb synaptosomes from dual transgenic lines with Dox consistently showed a slight but significant reduction in maximum mitochondrial respiration compared to controls. These results suggest that in the presence of increased oxidative stress, increased alpha-synuclein expression within dopaminergic OB neurons results in neurodegeneration in the glomerular layer (GL) and increased alpha-synuclein levels in the granular cell layer which coincide with olfactory dysfunction.
帕金森病（PD）涉及运动和非运动障碍。非运动特征包括感觉嗅觉功能的改变，这可能构成该疾病的可行生物标志物。嗅觉功能障碍的原因尚不清楚，但似乎与嗅球（OB）内的突触核蛋白病的发展同时发生。α-突触核蛋白（a-syn）的升高确实是散发性疾病发展的一个危险因素。特发性疾病的多因素性质及其表现的可变性表明，它可能受到多种因素的影响，并且探索α-突触核蛋白升高与其他潜在致病因素协同作用的体内模型可能对于理解疾病的发病机制很重要。我们使用多巴胺能α-突触核蛋白过表达的双重转基因（DTg）小鼠模型，结合这些细胞中的强力霉素（Dox）诱导的谷胱甘肽（GSH）耗竭，证明了与行为嗅觉功能相关的年龄相关性丧失，以及肾小球多巴胺能神经元的明显神经退行性变。这伴随着颗粒细胞层（GCL）中非多巴胺能细胞中α-突触核蛋白水平的增加。此外，来自具有 Dox 的双重转基因系的分离的嗅球突触小体始终显示与对照相比，最大线粒体呼吸的轻微但显著降低。这些结果表明，在增加的氧化应激存在下，多巴胺能 OB 神经元中增加的α-突触核蛋白表达导致肾小球层（GL）中的神经退行性变以及颗粒细胞层中α-突触核蛋白水平的增加，这与嗅觉功能障碍同时发生。
