Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression.
Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression.
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DOI：
10.1038/s41598-017-16690-x
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发表时间：
2017-11-27
影响因子：
4.6
通讯作者：
Sortwell CE
中科院分区：
文献类型：
--
作者：
Fischer DL;Manfredsson FP;Kemp CJ;Cole-Strauss A;Lipton JW;Duffy MF;Polinski NK;Steece-Collier K;Collier TJ;Gombash SE;Buhlinger DJ;Sortwell CE
丘脑底核脑深部电刺激（Subthalamic nucleus deep brain stimulation，DBS）可保护黑质多巴胺能神经元免受6-OHDA和MPTP的损伤。我们使用单侧黑质内注射重组腺相关病毒假型2/5以过表达野生型人α-突触核蛋白（rAAV 2/5 α-syn），在表现出α-突触核蛋白病理的帕金森病模型中评估了STN DBS。低滴度的rAAV 2/5 α-syn在8周后导致进行性前肢不对称、纹状体多巴胺能末端密度的损失和SNpc多巴胺神经元的适度损失，对应于稳健的人Snca表达，并且对大鼠Snca、Th、Bdnf或Trk 2没有影响。α-syn过表达增加了SNpc神经元中核糖体蛋白S6（p-rpS 6）的磷酸化，这是trkB激活的读数。大鼠接受黑质内注射rAAV 2/5 α-syn，3周后接受4周的DBS或电极植入，保持不活动。DBS不能防止α-syn介导的前肢运动不能、纹状体去神经支配或SNpc神经元丢失的缺陷，DBS也不能进一步升高p-rpS 6水平。ON刺激，前肢不对称性加剧，表明α-syn过表达介导的神经传递缺陷。这些结果表明，C3 DBS不能保护黑质纹状体系统免受α-syn过表达介导的毒性。在其他突触核蛋白病模型中，DBS是否具有保护作用尚不清楚。
Subthalamic nucleus deep brain stimulation (STN DBS) protects dopaminergic neurons of the substantia nigra pars compacta (SNpc) against 6-OHDA and MPTP. We evaluated STN DBS in a parkinsonian model that displays α-synuclein pathology using unilateral, intranigral injections of recombinant adeno-associated virus pseudotype 2/5 to overexpress wildtype human α-synuclein (rAAV2/5 α-syn). A low titer of rAAV2/5 α-syn results in progressive forelimb asymmetry, loss of striatal dopaminergic terminal density and modest loss of SNpc dopamine neurons after eight weeks, corresponding to robust human-Snca expression and no effect on rat-Snca, Th, Bdnf or Trk2. α-syn overexpression increased phosphorylation of ribosomal protein S6 (p-rpS6) in SNpc neurons, a readout of trkB activation. Rats received intranigral injections of rAAV2/5 α-syn and three weeks later received four weeks of STN DBS or electrode implantation that remained inactive. STN DBS did not protect against α-syn-mediated deficits in forelimb akinesia, striatal denervation or loss of SNpc neuron, nor did STN DBS elevate p-rpS6 levels further. ON stimulation, forelimb asymmetry was exacerbated, indicating α-syn overexpression-mediated neurotransmission deficits. These results demonstrate that STN DBS does not protect the nigrostriatal system against α-syn overexpression-mediated toxicity. Whether STN DBS can be protective in other models of synucleinopathy is unknown.
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影响因子：
5.3
作者：
Decressac, M.;Mattsson, B.;Bjorklund, A.
通讯作者：
Bjorklund, A.
影响因子：
2.9
作者：
Fang, Xin;Sugiyama, Kenji;Namba, Hiroki
通讯作者：
Namba, Hiroki
影响因子：
5.3
作者：
Harnack, Daniel;Meissner, Wassilios;Kupsch, Andreas
通讯作者：
Kupsch, Andreas
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
DOI：
10.1073/pnas.0711053105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Gorbatyuk, Oleg S.;Li, Shoudong;Muzyczka, Nicholas
通讯作者：
Muzyczka, Nicholas