Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury.
Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury.
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DOI：
10.1186/s40478-016-0375-7
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发表时间：
2016-10-03
影响因子：
7.1
通讯作者：
Volkmann J
中科院分区：
文献类型：
--
作者：
Ip CW;Isaias IU;Kusche-Tekin BB;Klein D;Groh J;O'Leary A;Knorr S;Higuchi T;Koprich JB;Brotchie JM;Toyka KV;Reif A;Volkmann J
孤立性全身性肌张力障碍是一种以扭曲的运动或姿势为特征的中枢运动网络障碍。最常见的遗传原因是编码 torsinA 的 Tor1a (DYT1) 基因中的 GAG 缺失，外显率降低了 30-40%，表明需要额外的遗传或环境修饰剂。通过尾部悬吊期间的后肢运动评分、旋转测试和计算机辅助步态分析，评估仅表达 50% torsinA 的野生型 (wt) 和 Tor1a+/- 小鼠标准化周围神经挤压损伤后肌张力障碍样运动的发展。对纹状体中的多巴胺转运蛋白 (DAT)、D1 和 D2 受体进行蛋白质印迹分析，并对中脑解剖中的 DAT 进行定量 RT-PCR 分析。使用放射自显影术评估纹状体中 DAT 的功能结合。通过高效液相色谱法分析纹状体多巴胺及其代谢物。神经挤压损伤后，我们发现突变型和野生型小鼠的受损后肢出现异常姿势，表明神经损伤的深远影响（相对于对照为 15 倍与 12 倍），类似于人类周围假性肌张力障碍。在突变小鼠中，表型异常增加了约 40% (p < 0.05)。这伴随着纹状体多巴胺稳态的复杂改变。多巴胺合成的药物阻断可减轻肌张力障碍样运动的严重程度，而左旋多巴治疗则加剧这些症状，但仅在突变小鼠中，这表明 DYT1 相关的核心成分与异常不自主运动的发展有关。我们的研究结果表明，周围神经损伤后，torsinA 浓度降低和环境应激源可能协同作用，导致 DYT1 肌张力障碍的中枢运动网络功能障碍。本文的在线版本 (doi:10.1186/s40478-016-0375-7) 包含补充材料，可供授权用户使用。
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia. The online version of this article (doi:10.1186/s40478-016-0375-7) contains supplementary material, which is available to authorized users.
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影响因子：
8.6
作者：
Albanese, Alberto;Bhatia, Kailash;Bressman, Susan B.;DeLong, Mahlon R.;Fahn, Stanley;Fung, Victor S. C.;Hallett, Mark;Jankovic, Joseph;Jinnah, Hyder A.;Klein, Christine;Lang, Anthony E.;Mink, Jonathan W.;Teller, Jan K.
通讯作者：
Teller, Jan K.
影响因子：
2.9
作者：
ABERCROMBIE, ED;BONATZ, AE;ZIGMOND, MJ
通讯作者：
ZIGMOND, MJ
影响因子：
6.1
作者：
Grundmann, K.;Reischmann, B.;Riess, O.
通讯作者：
Riess, O.
影响因子：
5
作者：
Hamann, M;Richter, A
通讯作者：
Richter, A
影响因子：
8.6
作者：
Garibotto, Valentina;Romito, Luigi M.;Perani, Daniela
通讯作者：
Perani, Daniela