Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (alphaSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons.
Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (alphaSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons.
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DOI：
10.1186/1750-1326-4-34
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发表时间：
2009-07-24
影响因子：
15.1
通讯作者：
Moore DJ
中科院分区：
文献类型：
--
作者：
Daher JP;Ying M;Banerjee R;McDonald RS;Hahn MD;Yang L;Flint Beal M;Thomas B;Dawson VL;Dawson TM;Moore DJ
α-突触核蛋白基因的错义突变和倍增导致常染色体显性遗传性家族性帕金森病(PD)。α-突触核蛋白也是路易小体的主要成分，路易小体是帕金森病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帕金森病的发病机制中起重要作用。为了在体内模拟α-突触核蛋白连锁疾病，已经建立了转基因小鼠模型，表达来自各种神经元选择性异源启动子元件的野生型或突变型人α-突触核蛋白。这些模型表现出许多类似帕金森病某些方面的行为和神经病理特征。然而，这些模型的一个重要缺陷是观察到缺乏强健的或进行性的黑质纹状体多巴胺能神经元变性，这是帕金森病的特征。我们已经发展出条件性α-突触核蛋白转基因小鼠，能够以Cre重组酶依赖的方式表达内源性小鼠ROSA26启动子的A53T、E46K或C末端截短(1-119)的人α-突触核蛋白病理变体。利用这些小鼠，我们评估了这些α-突触核蛋白变体的表达对黑质多巴胺能神经元随年龄增长的完整性和活性的影响。选择性地在黑质纹状体通路多巴胺能神经元中表达A53Tα突触核蛋白或截短的α突触突触后12个月，不能促进这些小鼠的多巴胺能神经元的丢失。然而，在黑质多巴胺能神经元中表达αSyn119长达12个月会导致纹状体多巴胺及其代谢物水平显著下降，并伴随着其他微妙的神经化学变化。我们已经建立并评价了一种新型的条件性α-突触核蛋白转基因小鼠，该转基因小鼠选择性地针对黑质纹状体多巴胺能神经元进行转基因表达，作为一种潜在的新的帕金森病小鼠模型。我们的数据支持C末端截短的α-突触核蛋白物种在体内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纹状体多巴胺耗竭的有用模型，并可能提供帕金森病症状前模型，可能代表神经元丧失之前观察到的最早的多巴胺能神经元功能紊乱。这些条件性α-突触核蛋白转基因小鼠为评估和解剖α-突触核蛋白病理变异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。
Missense mutations and multiplications of the α-synuclein gene cause autosomal dominant familial Parkinson's disease (PD). α-Synuclein protein is also a major component of Lewy bodies, the hallmark pathological inclusions of PD. Therefore, α-synuclein plays an important role in the pathogenesis of familial and sporadic PD. To model α-synuclein-linked disease in vivo, transgenic mouse models have been developed that express wild-type or mutant human α-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 α-synuclein transgenic mice that can express A53T, E46K or C-terminally truncated (1–119) human α-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 α-synuclein variants on the integrity and viability of nigral dopaminergic neurons with age. Expression of A53T α-synuclein or truncated αSyn119 selectively in nigrostriatal pathway dopaminergic neurons for up to 12 months fails to precipitate dopaminergic neuronal loss in these mice. However, αSyn119 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 α-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 α-synuclein species in vivo. The expression of αSyn119 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 α-synuclein transgenic mice provide novel tools for evaluating and dissecting the age-related effects of α-synuclein pathological variants on the function of the nigrostriatal dopaminergic pathway or other specific neuronal populations.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
4.8
作者：
Liu, CW;Giasson, BI;Thomas, PJ
通讯作者：
Thomas, PJ
影响因子：
2.9
作者：
Mishizen-Eberz, AJ;Norris, EH;Lynch, DR
通讯作者：
Lynch, DR
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T