Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

富含亮氨酸的重复蛋白激酶2(LRRK2)突变是遗传性帕金森病与年龄相关的外显性疾病的原因。该蛋白是一种复杂的大分子蛋白，具有多种已知的蛋白相互作用和多种功能。一些突变会增加激酶活性，本项目的总体目标是扩大我们先前的观察结果，即LRRK2的激酶活性在与该基因突变相关的发病机制中起重要作用。 在过去的报告期间，我们花了一些时间鉴定高纯度的LRRK2蛋白和相关的同源物LRRK1。我们发现，这两种蛋白质都形成二聚体，这是我们之前提出的，但一直存在争议。我们正在探索的一种可能性是，LRRK2的蛋白质结合伙伴和/或构象状态阻止了这种情况在细胞内发生。我们还能够用部分纯化的材料证实我们之前的观察结果，即与帕金森氏病相关的LRRK2蛋白是一种比同系物LRRK1更活跃的蛋白。这一观察结果的意义尚不清楚。 我们还鉴定了LRRK2的一个危险因子变体G2385R，我们意外地发现它的激酶活性低于野生型蛋白。可能的机制是G2385R改变了大而复杂的蛋白质内的分子内相互作用。这项工作可能会对应该为LRRK2相关疾病开发的治疗方法类型产生影响。

Leucine rich repeat kinase 2 (LRRK2) mutations are causal for inherited Parkinsons disease with age-dependent penetrance. The protein is a large complex kinase with several reported protein interactions and mutliple proposed functions. Some mutations increase kinase activity, and the overall aim of this project is to extend our prior observations that kinase activity of LRRK2 is important in pathogenesis association with mutations in this gene. In the past reporting period, we have spent some time characterizing highly purified LRRK2 protein, and the related homolog LRRK1. We find that both proteins form dimers, which we had previously suggested but has been controversial. One possibility, which we are pursuing, is that there are protein binding partners and/or conformational states of LRRK2 that prevent this from happening within cells. We were also able to confirm our previous observations with partially purified material, that the Parkinson's disease associated LRRK2 protein is a more active kinase than the homolog LRRK1. The significance of this observation is not yet clear. We have also characterized a risk factor variant for LRRK2, G2385R, which we found surprisingly has lower kinase activity than wild type protein. The likely mechanism is that G2385R alters intramolecular interactions within the large, complex protein. This work may have implications for the types of therapeutics that should be developed for LRRK2-related disease.