Towards a unifying theory of Parkinson's disease: Investigation of the biochemical and genetic role of Rab GTPases

LRRK2和PINK1基因的突变可以在帕金森家族患者中遗传。LRRK2和PINK1是一种特殊的酶，被称为蛋白激酶，其作用是用一个化学磷酸基团标记目标蛋白质(在一个被称为磷酸化的过程中)。我们的实验室以前在了解LRRK2和PINK1的功能方面取得了重大进展，最近发现这些酶针对一种不同类型的酶，称为RAB GTP酶。我们现在希望更好地了解LRRK2和PINK1如何控制RAB，以及这些酶的突变如何影响细胞中的RAB功能。为了实现这一目标，我们的目标是确定由LRRK2和PINK1控制的关键RAB，并发现RAB结合的分子，以便在细胞中执行下游通信。为了补充我们的分析，我们将与遗传学研究人员合作，确定RAB本身是否在帕金森氏症家族中发生突变。这个项目将导致对LRRK2和PINK1控制的细胞通路的基本理解，并提高我们对帕金森氏症影响的关键通路的理解。

Mutations in the LRRK2 and PINK1 genes can be inherited in patients with familial forms of Parkinson's. LRRK2 and PINK1 function as a special class of enzymes known as protein kinases whose job is to label target proteins with a chemical phosphate group (in a process known as phosphorylation). Our laboratories have previously made significant advances in understanding the function of LRRK2 and PINK1 and recently identified that these enzymes target a different class of enzymes known as Rab GTPases. We now wish to better understand how LRRK2 and PINK1 controls Rabs and how mutations in these enzymes impact on Rab functioning in cells. Towards this goal we aim to identify the key Rabs controlled by LRRK2 and PINK1 and discover the molecules that Rabs bind to in order to execute downstream communications in the cell. To complement our analysis we will collaborate with genetics researchers to determine if Rabs themselves are mutated in families with Parkinson's. This project will lead to a fundamental understanding of the cellular pathways controlled by LRRK2 and PINK1 and improve our understanding of the critical pathways affected in Parkinson's.