Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

富含亮氨酸重复序列激酶2（LRRK 2）突变是遗传性帕金森病伴年龄依赖性痴呆的病因。该蛋白是一个大的复杂激酶，具有几种已报道的蛋白质相互作用和多种功能。一些突变增加激酶活性，本项目的总体目标是扩展我们先前的观察，即LRRK 2的激酶活性在与该基因突变相关的发病机制中很重要。 在过去的报告期间，我们花了一些时间表征高度纯化的LRRK 2蛋白和相关的同系物LRRK 1。我们发现，这两种蛋白质形成二聚体，这是我们以前提出的，但一直存在争议。我们正在追求的一种可能性是，存在蛋白质结合伴侣和/或LRRK 2的构象状态，可以防止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先前的观察结果，即帕金森病相关的LRRK 2蛋白是比同系物LRRK 1更活跃的激酶。这一观察结果的意义尚不清楚。 我们还表征了LRRK 2的风险因子变体G2385 R，我们惊奇地发现其具有比野生型蛋白更低的激酶活性。可能的机制是G2385 R改变了大的复杂蛋白质内的分子内相互作用。这项工作可能会对LRRK 2相关疾病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.