Physiology of mitochondrial dysfunction in genetic models of Parkinson's disease

我们已经开始研究发生在转基因小鼠中的神经退行性变，这是由我们在瑞典卡罗林斯卡研究所的合作者开发的。 我们现在已经在我们的研究所建立了一个成功的这些小鼠的繁殖群，我们已经把它们提供给我们当地的合作者。 这些小鼠在线粒体基因中具有称为线粒体转录因子A（tFam）的突变。 该基因调节所有细胞中的线粒体DNA转录，并且是持续氧化磷酸化所必需的。 然而，通过使用驱动多巴胺转运蛋白表达的启动子将这种突变靶向多巴胺神经元，只有这些神经元受到突变的影响。 我们目前的工作表明，DA神经元在30周内缓慢退化，并且小鼠显示出人类帕金森病的许多特征。 这包括对药物治疗（如左旋多巴治疗）的敏感性，以及随着神经退行性疾病的进展而丧失这种治疗益处。 我们的研究还表明，胶质细胞源性神经营养因子（GDNF）通过腺相关病毒（AAV）的表达可以节省这些多巴胺神经元，并防止神经毒素或遗传诱导的帕金森病小鼠。 此外，在用多巴胺神经毒素MPTP进行的试点研究中，我们发现多巴胺的损失引起纹状体生理特性的深刻变化，这也被AAV介导的GDNF基因表达所阻止。 我们现在将开始在帕金森病的tFam遗传模型中测试这种形式的基因治疗，并尝试在疾病进展期间的不同时间点逆转神经变性。

We have begun to examine the neurodegeneration that occurs in a genetically modified mouse that was developed by our collaborators at the Karolinska Institute in Sweden. We have now established a successful breeding colony of these mice at our institute, and we have made them available to our local collaborators. These mice possess a mutation in the mitochondrial gene known as mitochondrial transcription factor A (tFam). This gene regulates mitochondrial DNA transcription in all cells, and is necessary for continued oxidative phosphorylation. However, by targeting this mutation to dopamine neurons using the promoter that drives dopamine transporter expression, only these neurons are affected by the mutation. Our present work shows that the DA neurons degenerate slowly over a 30 week period, and that the mice display many hallmarks of Parkinsons disease in humans. This includes sensitivity to pharmacological treatments, such as L-Dopa therapy, and the loss of this therapeutic benefit as the neurodegeneration progresses. Our studies have also shown that expression of glial cell line-derived neurotrophic factor (GDNF) through adeno-associated virus (AAV) can spare these dopamine neurons, and protect against either neurotoxin or genetically induced parkinsonism in mice. In addition, in pilot studies conducted with the dopamine neurotoxin MPTP, we have found that the loss of dopamine causes profound changes in the physiological properties of the striatum that were also prevented by AAV-mediated gene expression of GDNF. We will now begin to test this form of gene therapy in the tFam genetic model of Parkinsons disease, and attempt to reverse the neurodegeneration at various time points during the disease progression.