NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, USA.
Mol Neurodegener. 2009 Jul 24;4:34. doi: 10.1186/1750-1326-4-34.
Missense mutations and multiplications of the alpha-synuclein gene cause autosomal dominant familial Parkinson's disease (PD). alpha-Synuclein protein is also a major component of Lewy bodies, the hallmark pathological inclusions of PD. Therefore, alpha-synuclein plays an important role in the pathogenesis of familial and sporadic PD. To model alpha-synuclein-linked disease in vivo, transgenic mouse models have been developed that express wild-type or mutant human alpha-synuclein from a variety of neuronal-selective heterologous promoter elements. These models exhibit a variety of behavioral and neuropathological features resembling some aspects of PD. However, an important deficiency of these models is the observed lack of robust or progressive nigrostriatal dopaminergic neuronal degeneration that is characteristic of PD.
We have developed conditional alpha-synuclein transgenic mice that can express A53T, E46K or C-terminally truncated (1-119) human alpha-synuclein pathological variants from the endogenous murine ROSA26 promoter in a Cre recombinase-dependent manner. Using these mice, we have evaluated the expression of these alpha-synuclein variants on the integrity and viability of nigral dopaminergic neurons with age. Expression of A53T alpha-synuclein or truncated alphaSyn119 selectively in nigrostriatal pathway dopaminergic neurons for up to 12 months fails to precipitate dopaminergic neuronal loss in these mice. However, alphaSyn119 expression in nigral dopaminergic neurons for up to 12 months causes a marked reduction in the levels of striatal dopamine and its metabolites together with other subtle neurochemical alterations.
We have developed and evaluated novel conditional alpha-synuclein transgenic mice with transgene expression directed selectively to nigrostriatal dopaminergic neurons as a potential new mouse model of PD. Our data support the pathophysiological relevance of C-terminally truncated alpha-synuclein species in vivo. The expression of alphaSyn119 in the mouse nigrostriatal dopaminergic pathway may provide a useful model of striatal dopamine depletion and could potentially provide a presymptomatic model of PD perhaps representative of the earliest derangements in dopaminergic neuronal function observed prior to neuronal loss. These conditional alpha-synuclein transgenic mice provide novel tools for evaluating and dissecting the age-related effects of alpha-synuclein pathological variants on the function of the nigrostriatal dopaminergic pathway or other specific neuronal populations.
α-突触核蛋白基因突变和扩增会导致常染色体显性遗传家族性帕金森病（PD）。α-突触核蛋白也是路易体的主要成分，路易体是 PD 的标志性病理包涵体。因此，α-突触核蛋白在家族性和散发性 PD 的发病机制中起重要作用。为了在体内模拟与 α-突触核蛋白相关的疾病，已经开发了表达野生型或突变型人α-突触核蛋白的转基因小鼠模型，这些模型使用各种神经元选择性异源启动子元件。这些模型表现出多种类似于 PD 的行为和神经病理学特征。然而，这些模型的一个重要缺陷是观察到缺乏 PD 特征性的黑质纹状体多巴胺能神经元进行性退化。
我们已经开发了条件性α-突触核蛋白转基因小鼠，这些小鼠可以在 Cre 重组酶依赖性的方式下，从内源性鼠 ROSA26 启动子表达 A53T、E46K 或 C 端截断（1-119）的人类α-突触核蛋白病理变异体。使用这些小鼠，我们评估了这些α-突触核蛋白变异体随年龄对黑质多巴胺能神经元完整性和活力的影响。在长达 12 个月的时间内，A53T α-突触核蛋白或截断的αSyn119 选择性地在黑质纹状体通路多巴胺能神经元中表达，不会导致这些小鼠中多巴胺能神经元丢失。然而，长达 12 个月的αSyn119 在黑质多巴胺能神经元中的表达会导致纹状体多巴胺及其代谢物水平显著降低，同时还伴有其他微妙的神经化学改变。
我们已经开发并评估了新型的条件性α-突触核蛋白转基因小鼠，其转基因表达定向到黑质纹状体多巴胺能神经元，作为一种潜在的新的 PD 小鼠模型。我们的数据支持体内 C 端截断的α-突触核蛋白物种的病理生理学相关性。αSyn119 在小鼠黑质纹状体多巴胺能通路中的表达可能提供一种纹状体多巴胺耗竭的有用模型，并且可能提供一种 PD 的亚临床前模型，也许代表了在神经元丢失之前观察到的多巴胺能神经元功能最早紊乱之前的情况。这些条件性α-突触核蛋白转基因小鼠为评估和剖析α-突触核蛋白病理变异体对黑质纹状体多巴胺能通路或其他特定神经元群体功能的年龄相关影响提供了新的工具。
