A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.
A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.
复制标题
DOI：
10.1371/journal.pone.0011464
复制
发表时间：
2010-07-07
期刊：
影响因子：
3.7
通讯作者：
Gispert S
中科院分区：
文献类型：
--
作者：
Kurz A;Double KL;Lastres-Becker I;Tozzi A;Tantucci M;Bockhart V;Bonin M;García-Arencibia M;Nuber S;Schlaudraff F;Liss B;Fernández-Ruiz J;Gerlach M;Wüllner U;Lüddens H;Calabresi P;Auburger G;Gispert S
帕金森氏病（PD）是老年人第二常见的神经退行性疾病，可由突触前蛋白α-突触核蛋白（SNCA）的表达升高或A53 T错义突变引起。PD的病理特征是多巴胺能黑质纹状体投射神经元的优先脆弱性。在这里，我们使用了两种过表达人类A53 T-SNCA的小鼠品系，并在没有神经变性的情况下研究了纹状体功能障碍，以了解早期疾病机制。为了表征进展，我们采用了年轻的成年小鼠和老年小鼠。纹状体神经递质含量的分析表明，多巴胺（DA）水平与SNCA的表达水平直接相关，在SNCA缺陷（敲除，KO）小鼠中也观察到了这一点。然而，鉴于三个观察结果，A53 T-SNCA过表达的老年小鼠纹状体中升高的DA水平可能不会被适当地传递。首先，发现神经DA降解酶儿茶酚邻甲基转移酶（COMT）的转录下调。其次，通过免疫印迹和放射自显影检测到DA受体的上调。第三，通过微阵列和定量实时RT-PCR（qPCR）的DA诱导基因Atf 2，Cb 1，Freq，Homer 1和Pde 7 b的转录水平改变的广泛的转录组研究表明，突触后DA反应的进行性和基因型依赖性减少。作为一个功能的结果，长期抑郁症（LTD）是不存在的皮质纹状体切片从老年转基因小鼠。总之，在A53 T-SNCA过表达小鼠中观察到的功能失调的神经传递和受损的突触可塑性反映了基底神经节在明显神经变性之前的早期变化。作为PD临床前阶段的模型，这些见解可能有助于开发神经保护性治疗方法。
Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice. Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.
登录
查看更多内容
影响因子：
25
作者：
Giuffrida, A;Parsons, LH;Piomelli, D
通讯作者：
Piomelli, D
影响因子：
5.3
作者：
Calabresi, P;Gubellini, P;Bernardi, G
通讯作者：
Bernardi, G
影响因子：
2.9
作者：
Lastres-Becker, I;Berrendero, F;Fernández-Ruiz, JJ
通讯作者：
Fernández-Ruiz, JJ
影响因子：
5.3
作者：
Kuwajima, Masaaki;Dehoff, Marlin H.;Smith, Yoland
通讯作者：
Smith, Yoland
影响因子：
14.9
作者：
Gründemann J;Schlaudraff F;Haeckel O;Liss B
通讯作者：
Liss B