DNAJC6/Auxilin mutations and Parkinson's disease

我们使用基因组编辑在人类和小鼠基因组中引入与家族性早发性复杂形式帕金森病（PD）相关的基因DNAJC 6突变。由于编码的蛋白质，生长素，在神经元中表达，我们已经集中在显示行为是如何受到突变的影响。随着年龄的增长，小鼠表现出微妙但重要的运动表型。我们没有神经元的损失，这表明神经元功能障碍的发生没有明显的神经变性。从机制上讲，我们发现突变允许与网格蛋白相互作用，但不允许与突触和高尔基体上存在的网格蛋白接头蛋白相互作用。我们看到脂质积累可能与高尔基体功能障碍有关，尽管目前还没有得到证实。我们在这个项目中正在进行的工作将是进一步开发一个更具侵略性的模型，具有更强的神经退行性表型。

We have used genome editing to introduce mutations in the human and mouse genome in the gene DNAJC6 that are associated with a familial, early onset complex form of Parkinson's disease (PD). Because the encoded protein, auxilin, is expressed in neurons, we have focussed on showing how behavior is affected by mutations. Mice show a subtle but significant motor phenotype as they age. We do not loss of neurons, suggesting that neuronal dysfunction occurs without overt neurodegeneration. Mechanistically, we have found that mutations allow for interaction with clathrin but not clathrin adaptor proteins that are present at both synapse and the Golgi. We see lipid accumulations that may relate to Golgi dysfunction, although this is not proven at this time. Our ongoing work in this project will be to further develop a more aggressive model with stronger neurodegenerative phenotypes.