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。当前治疗 这些方法最初可以缓解症状，但最终会导致有害的副作用， 进展一个重要的遗传成分疾病最近被确定为突变的leucirierich 重复激酶2基因（LRRK2）。LRRK2突变导致高度外显显性疾病 表型与典型PD无区别。初步数据表明，LRRK2突变扰乱了细胞的生长。 LRRK2的正常酶活性通过增加激酶活性。激酶活性的这种增加是 与神经毒性有关。该提案的指导阶段使用以下方法剖析LRRK2毒性： 包括诱导型基因表达、RNA干扰和病毒递送的方法的组合， 突变LRRK到原代神经元。目的是确定LRRK2介导的激酶依赖性细胞死亡 瀑布了解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中的第一个， LRRK2激酶底物将使用新技术的组合来鉴定，以评估LRRK2激酶的活性。 完整的LRRK2相互作用蛋白。LRRK2的功能影响 介导的激酶对蛋白质底物的活性将进行评估，特别是在现有的和新兴的 PD模型最后，第二个独立阶段的目标是利用开发的工具和技术， 这一建议进行高通量筛选，以确定小分子LRRK2激酶抑制剂。 小分子抑制剂将用于明确评估LRRK2激酶活性在引起LRRK2激酶抑制中的作用。 神经毒性LRRK2可能代表PD发病机制中的远上游元件。通过 了解LRRK2，参与PD的其他基因可能属于共同的生化途径， 疾病干预是可能的。 富含亮氨酸重复序列激酶2（LRRK2）基因突变是帕金森病的常见原因。 该提案探讨了LRRK2在神经退行性变中的作用，重点是识别通路， 药物干预疾病进程。

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.