An α-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson's disease, but displays toxicity in dopamine neurons.
An α-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson's disease, but displays toxicity in dopamine neurons.
复制标题
DOI：
10.1016/j.brainres.2011.04.036
复制
发表时间：
2011-06-13
期刊：
影响因子：
2.9
通讯作者：
Bohn MC
中科院分区：
文献类型：
--
作者：
Khodr CE;Sapru MK;Pedapati J;Han Y;West NC;Kells AP;Bankiewicz KS;Bohn MC
研究了沉默大鼠黑质（SN）中异位表达的hSNCA作为治疗帕金森病（PD）的新方法的作用。将AAV-hSNCA（含或不含含靶向hSNCA或荧光素酶的短发夹RNA的AAV）注射到一个SN中。在9周时，表达hsnca的大鼠SN多巴胺（DA）神经元减少，并表现出前肢缺陷。AAV-shRNA-SNCA沉默hSNCA并保护前肢缺陷。然而，AAV-shRNA-SNCA也导致DA神经元丢失，提示慢性shRNA表达的不良影响。使用逆行束示踪剂检测对黑质纹状体突起神经元的影响。在载体注射部位，纹状突起的DA神经元明显丢失，而在表达hsnca的大鼠中，该部位外的DA神经元丢失，而在hsnca沉默的大鼠中则没有。这些观察结果表明，高水平的shRNA-SNCA对DA神经元是有毒的，而暴露于低水平的邻近神经元则受到hSNCA基因沉默的保护。此外，收集到的DA水平数据表明，除黑质纹状体DA神经元外，还有其他神经元对前肢使用的保护也有贡献。我们的观察结果表明，虽然DA神经元中的hSNCA基因沉默有望成为一种新的PD治疗方法，但需要进一步发展沉默技术。
Effects of silencing ectopically expressed hSNCA in rat substantia nigra (SN) were examined as a novel therapeutic approach to Parkinson’s disease (PD). AAV-hSNCA with or without an AAV harboring a short-hairpin (sh)RNA targeting hSNCA or luciferase was injected into one SN. At 9wks, hSNCA-expressing rats had reduced SN dopamine (DA) neurons and exhibited a forelimb deficit. AAV-shRNA-SNCA silenced hSNCA and protected against the forelimb deficit. However, AAV-shRNA-SNCA also led to DA neuron loss suggesting undesirable effects of chronic shRNA expression. Effects on nigrostriatal-projecting neurons were examined using a retrograde tract tracer. Loss of striatal-projecting DA neurons was evident in the vector injection site, whereas DA neurons outside this site were lost in hSNCA-expressing rats, but not in hSNCA-silenced rats. These observations suggest that high levels of shRNA-SNCA were toxic to DA neurons, while neighboring neurons exposed to lower levels were protected by hSNCA gene silencing. Also, data collected on DA levels suggest that neurons other than or in addition to nigrostriatal DA neurons contributed to protection of forelimb use. Our observations suggest that while hSNCA gene silencing in DA neurons holds promise as a novel PD therapy, further development of silencing technology is required.
登录
查看更多内容
影响因子：
2.9
作者：
Björklund, A;Kirik, D;Mandel, RJ
通讯作者：
Mandel, RJ
DOI：
10.1073/pnas.0800803105
发表时间：
2008-07-08
影响因子：
11.1
作者：
Diederichs, Sven;Jung, Stephanie;Habert, Daniel A.
通讯作者：
Habert, Daniel A.
影响因子：
64.8
作者：
Grimm, Dirk;Streetz, Konrad L.;Kay, Mark A.
通讯作者：
Kay, Mark A.
影响因子：
4.8
作者：
Doxakis, Epaminondas
通讯作者：
Doxakis, Epaminondas
影响因子：
5.3
作者：
Fleming, SM;Salcedo, J;Chesselet, MF
通讯作者：
Chesselet, MF