Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease
Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease
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DOI：
10.1038/mt.2010.217
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发表时间：
2011-01-01
影响因子：
12.4
通讯作者：
Tansey, Malu G.
中科院分区：
文献类型：
--
作者：
Harms, Ashley S.;Barnum, Christopher J.;Tansey, Malu G.
帕金森病（Parkinson's disease，PD）是一种进行性神经退行性疾病，其特征是黑质多巴胺能（dopaminergic，DA）神经元丢失。最近的证据表明，神经炎症，特别是肿瘤坏死因子（TNF）可能在PD的发病机制中发挥关键作用。我们先前已经表明，可溶性TNF（solTNF）是介导6-羟基多巴胺（6-OHDA）或脂多糖诱导的稳健变性所必需的。目前尚不清楚的是，TNF抑制是否可以减轻神经变性的延迟和进行性阶段。为了测试这一点，在接受6-OHDA损伤后2周，向大鼠的SNpc中注射编码显性阴性TNF的慢病毒（lenti-DN-TNF）。值得注意的是，当在最初的6-OHDA损伤后5周检查时，没有观察到黑质DA神经元的进一步损失。Lenti-DN-TNF还减弱小胶质细胞活化。总之，这些数据表明，TNF可能是黑质DA神经元死亡的延迟和进行性阶段的神经退行性疾病的关键介质，小胶质细胞可能是主要的细胞类型。这些令人鼓舞的发现为在非人灵长类动物中进行DN-TNF基因转移研究提供了令人信服的理由，其长期目标是在临床中使用它来预防引起PD运动症状的DA神经元的延迟和进行性变性。
Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD.