The Role of LRRK2 in the Pathogenesis of Parkinson's Disease

帕金森病(PD)是一种常见的进行性神经退行性疾病。目前的治疗方法 治疗方法最初会缓解症状，但最终会产生有害的副作用，并未能阻止疾病 进步。疾病的一个重要遗传成分最近被确定为Leucirierich突变 重复蛋白激酶2基因(LRRK2)。LRRK2突变导致一种高度渗透性显性疾病 表型与典型的帕金森病难以区分。初步数据表明，LRRK2突变扰乱了 LRRK2的正常酶活性是通过增加激酶活性实现的。这种激酶活性的增加是 与神经毒性有关。该提案的指导阶段使用一种 多种方法的结合，包括可诱导的基因表达、RNA干扰和病毒传递 突变的LRRK到原代神经元。我们的目标是定义LRRK2介导的依赖于激酶的细胞死亡 瀑布。对理解LRRK2在健康和疾病中的作用的补充将是 相关细胞中LRRK2激酶底物的鉴定。作为两个独立阶段项目的第一阶段， 将使用新技术的组合来鉴定LRRK2激酶底物，以评估 一套完整的LRRK2相互作用蛋白，以无偏见的方式。LRRK2的功能影响 将评估蛋白底物上的介导的激酶活性，特别是在现有的和新兴的 帕金森病的模型。最后，第二个独立阶段的AIM使用在 这项建议进行高通量筛选，以确定小分子LRRK2激酶抑制剂。 小分子抑制剂将被用于明确评估LRRK2激酶活性在导致 神经毒性。LRRK2可能是帕金森病发病机制中的一个远上游元件。通过 了解LRRK2，参与PD的其他基因可能属于共同的生化途径，其中 疾病干预是可能的。 富含亮氨酸的重复蛋白激酶2(LRRK2)基因突变是帕金森氏症的常见原因。 这项建议探讨了LRRK2在神经退行性变中的作用，重点是识别通路和 干预疾病过程的药物。

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. Current therapeutic approaches initially alleviate symptoms but eventually cause deleterious side effects and fail to halt disease progression. A significant genetic component to disease was recently identified as mutations in the leucirierich repeat kinase 2 gene (LRRK2). LRRK2 mutations cause a highly-penetrant dominant disease phenotype indistinguishable from typical PD. Preliminary data suggest that LRRK2 mutations perturb the normal enzymatic activity of LRRK2 by increasing kinase activity. Such increases in kinase activity are associated with neurotoxicity. The mentored phase of this proposal dissects LRRK2 toxicity using a combination of approaches including inducible gene expression, RNA interference, and viral-delivery of mutant LRRK to primary neurons. The goal is to define LRRK2-mediated kinase dependent cell death cascades. Complementary to understanding the role of LRRK2 in health and disease will be the identification of LRRK2 kinase substrates in relevant cells. As the first of two independent phase projects, LRRK2 kinase substrates will be identified using a combination of novel technologies to assess the complete set of LRRK2 interacting proteins in an unbiased manner. The functional impact of LRRK2 mediated kinase activity on protein substrates will be evaluated, particularly in existing and emerging models of PD. Finally, the second independent phase aim utilizes the tools and techniques developed in this proposal to perform high-throughput screening to identify small-molecule LRRK2 kinase inhibitors. Small molecule inhibitors will be used to definitively assess the role of LRRK2 kinase activity in causing neurotoxicity. LRRK2 may represent a far upstream element in the pathogenesis of PD. Through the understanding of LRRK2, other genes involved in PD may fall into a common biochemical pathway where disease intervention is possible. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of Parkinson's disease. This proposal explores the role of LRRK2 in neurodegeneration with a focus on identifying pathways and drugs to intervene in the disease process.