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

迈向帕金森病的统一理论：Rab GTPases 生化和遗传作用的研究

• 批准号: MR/P00704X/1
• 负责人: Dario Alessi
• 金额: $ 30.68万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP00704X%2F1
• 关键词: Towards; unifying; theory; Parkinson; disease

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.

LRRK2和PINK1基因的突变可以在家族性帕金森病患者中遗传。LRRK2和PINK1作为一类特殊的酶，称为蛋白激酶，其工作是用化学磷酸基团标记靶蛋白（在称为磷酸化的过程中）。我们的实验室以前在理解LRRK2和PINK1的功能方面取得了重大进展，最近发现这些酶靶向另一类称为Rab GTP酶的酶。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Rab在细胞中的功能。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Rabs，并发现Rabs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，以确定Rabs本身是否在帕金森氏症家族中发生突变。该项目将导致对LRRK2和PINK1控制的细胞通路的基本理解，并提高我们对帕金森病影响的关键通路的理解。

项目成果

Supplementary Figures;Supplementary Table 1 from Mapping of a N-terminal a-helix domain required for human PINK1 stabilization, Serine228 autophosphorylation and activation in cells

补充图；补充表 1 来自细胞中人 PINK1 稳定、丝氨酸 228 自磷酸化和激活所需的 N 末端 a 螺旋结构域的映射

• DOI: 10.6084/m9.figshare.17429339
• 发表时间: 2022
• 作者: Kakade P

Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity.

• DOI: 10.1042/bcj20200458
• 发表时间: 2020-11-27
• 期刊: The Biochemical journal
• 作者: Kalogeropulou AF;Freemantle JB;Lis P;Vides EG;Polinski NK;Alessi DR
• 通讯作者: Alessi DR

LRRK2 activation in idiopathic Parkinson's disease.

• DOI: 10.1126/scitranslmed.aar5429
• 发表时间: 2018-07-25
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Di Maio R;Hoffman EK;Rocha EM;Keeney MT;Sanders LH;De Miranda BR;Zharikov A;Van Laar A;Stepan AF;Lanz TA;Kofler JK;Burton EA;Alessi DR;Hastings TG;Greenamyre JT
• 通讯作者: Greenamyre JT

Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils.

• DOI: 10.1042/bcj20170803
• 发表时间: 2018-01-02
• 期刊: The Biochemical journal
• 作者: Fan Y;Howden AJM;Sarhan AR;Lis P;Ito G;Martinez TN;Brockmann K;Gasser T;Alessi DR;Sammler EM
• 通讯作者: Sammler EM

Mapping of a N-terminal a-helix domain required for human PINK1 stabilisation, Serine228 autophosphorylation and activation in cells

绘制细胞中人 PINK1 稳定、丝氨酸 228 自磷酸化和激活所需的 N 端 a 螺旋结构域

• DOI: 10.1101/2021.09.06.459138
• 发表时间: 2021
• 作者: Kakade P