DNAJC6/Auxilin mutations and Parkinson's disease

DNAJC6/Auxilin 突变与帕金森病

• 批准号: 10688826
• 负责人: Mark Cookson
• 金额: $ 83.63万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688826
• 关键词: Adaptor Signaling Protein; Affect; Age; Auxilins; Behavior; Clathrin; Complex; Functional disorder; Genes; Goals; Golgi Apparatus; Human; Human Genome; Lipids; Modeling; Motor; Mus; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Parkinson Disease; Phenotype; Physiological; Proteins; Synapses; Time; Work; early onset; genome editing; mouse genome; neurodegenerative phenotype; protein function; protein protein interaction

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.

我们使用基因组编辑在人类和小鼠基因组中引入DNAJC6基因突变，这些突变与一种家族性、早发性复杂形式的帕金森病(PD)有关。由于编码蛋白质--生长素在神经元中表达，我们专注于展示突变是如何影响行为的。随着年龄的增长，小鼠表现出一种微妙但显著的运动表型。我们没有丢失神经元，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突触和高尔基体中同时存在的笼状蛋白相互作用，但不允许与笼状蛋白适配器蛋白相互作用。我们看到脂质堆积可能与高尔基体功能障碍有关，尽管这一点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具有更强神经退行性表型的更具侵略性的模型。