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LRRK2, KIF5A and Parkinson disease

LRRK2、KIF5A 和帕金森病

基本信息

批准号：
9920786
负责人：
WANLI W SMITH
金额：
$ 41.63万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920786
关键词：
Autophagocytosis Autophagosome Axon Axonal Transport Biological Clinical Cytoskeleton Defect Degenerative Disorder Development Disease Family member GTP Binding Genetic Guanosine Triphosphate Phosphohydrolases Hereditary Spastic Paraplegia Human Impairment In Vitro Intervention Investigation Kinesin Knock-out Knockout Mice LRRK2 gene Lewy body pathology Link Lysosomes Maps Mediating Microtubules Mitochondria Modeling Molecular Monitor Motor Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organelles Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Pharmacology Phosphotransferases Play Population Property Proteins Reporting Role Small Interfering RNA Spinal Ganglia Synaptic Vesicles Testing Therapeutic Time Toxic effect Transgenic Organisms Tubulin Ubiquitin Variant Yeasts aggregation pathway brain tissue genetic approach imaging system in vivo Model inhibitor/antagonist insight knock-down link protein live cell imaging multicatalytic endopeptidase complex mutant nervous system disorder neuronal transport neurotoxicity new therapeutic target novel overexpression protein aggregation protein transport retrograde transport tool yeast two hybrid system

项目摘要

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause a genetic form of Parkinson's disease (PD) with pleomorphic pathology, and constitute one of the most common known causes of PD. LRRK2 is a large protein whose normal functions are still largely unknown although it has kinase and GTPase activities. Most though not all LRRK2 mutations alter GTPase or kinase activities. We have identified KIF5A (kinesin family member 5A) as a novel LRRK2 interactor in a yeast two-hybrid screen. KIF5A is a microtubule-associated force- producing motor protein that drives intracellular organelle transport. Our preliminary studies suggest that KIF5A alters LRRK2-induced neuronal degeneration and protein aggregation. Thus, investigation of the KIF5A/LRRK2 interaction could provide novel insight into the mechanisms of LRRK2 PD pathogenesis. In this proposal, we will test the hypothesis that the interaction of mutant LRRK2 with KIF5A impairs cellular transport and contributes to neuronal degeneration resulting in PD pathology. Our proposed Aims are as follows: Aim 1. We will further characterize the newly identified KIF5A and LRRK2 interaction using in vitro and in vivo models. Aim 2. We will examine whether KIF5A protects against LRRK2-induced neuronal toxicity. Aim 3. We will determine whether mutant LRRK2 alters KIF5A-mediated axon transport. Aim 4. We will investigate the roles of LRRK2 and KIF5A interaction in relation to Lewy body pathology and cellular aggregation pathways. These studies will provide new insights into LRRK2 functions and potential novel mechanisms underlying LRRK2- linked protein aggregation and neurodegeneration, and may have broader implications for neurological diseases related to impairment of cellular transport. Thus, these studies have the potential for significant impact and benefit the population suffering from PD and other neurodegenerative diseases. The understanding of transport-related pathogenesis may provide new targets for development of novel disease- modifying therapeutic strategies.

摘要：富含亮氨酸重复序列激酶2（LRRK 2）的突变导致遗传形式的帕金森病（PD），多形性病理，并且构成PD的最常见已知原因之一。LRRK 2是一种大蛋白质尽管其具有激酶和GT3活性，但其正常功能仍在很大程度上未知。虽然大多数并非所有的LRRK 2突变都改变GT α或激酶活性。我们已经鉴定了KIF 5A（驱动蛋白家族成员 5A）作为酵母双杂交筛选中的新型LRRK 2相互作用子。KIF 5A是一种微管相关力产生驱动细胞内细胞器运输的马达蛋白。我们的初步研究表明KIF 5A 改变LRRK 2诱导的神经元变性和蛋白质聚集。因此，调查 KIF 5A/LRRK 2相互作用可为LRRK 2 PD发病机制提供新的见解。在这我们将检验突变体LRRK 2与KIF 5A的相互作用损害细胞转运的假设并导致神经元变性，导致PD病理学。我们提出的目标如下：目标1。我们将使用体外和体内模型进一步表征新鉴定的KIF 5A和LRRK 2相互作用。目标2.我们将研究KIF 5A是否可以保护LRRK 2诱导的神经元毒性。目标3.我们将确定突变LRRK 2是否改变KIF 5A介导的轴突转运。目标4。我们将调查 LRRK 2和KIF 5A相互作用与路易体病理学和细胞聚集途径的关系。这些这些研究将为LRRK 2的功能和潜在的新机制提供新的见解。相关的蛋白质聚集和神经变性，并可能有更广泛的影响，神经与细胞运输受损有关的疾病。因此，这些研究具有重要的潜在意义。影响和受益于患有PD和其他神经退行性疾病的人群。的对转运相关发病机制的理解可能为新疾病的发展提供新的靶点- 修改治疗策略。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.

DOI：
10.1159/000510387
发表时间：
2020
期刊：
Neuro-degenerative diseases
影响因子：
0
作者：
Ning B;Guo G;Gu C;Xu J;Bibic A;He X;Liu H;Chen L;Wei Z;Duan W;Liu P;Lu H;van Zijl PCM;Ross CA;Smith W;Hua J
通讯作者：
Hua J

68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment.

68和FX2149减弱突变体LRRK2-R1441C诱导的神经运输障碍。

DOI：
10.3389/fnagi.2016.00337
发表时间：
2016
期刊：
Frontiers in aging neuroscience
影响因子：
4.8
作者：
Thomas JM;Li T;Yang W;Xue F;Fishman PS;Smith WW
通讯作者：
Smith WW

GTP-binding inhibitors increase LRRK2-linked ubiquitination and Lewy body-like inclusions.

GTP 结合抑制剂可增加 LRRK2 相关的泛素化和路易体样内含物。

DOI：
10.1002/jcp.29632
发表时间：
2020
期刊：
Journal of cellular physiology
影响因子：
5.6
作者：
Thomas,JosephM;Wang,Xiaobo;Guo,Gongbo;Li,Tianxia;Dai,Bingling;Nucifora,LeslieG;NuciforaJr,FrederickC;Liu,Zhaohui;Xue,Fengtian;Liu,Chunfeng;Ross,ChristopherA;Smith,WanliW
通讯作者：
Smith,WanliW

The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration.

果蝇 hep 通路介导 Lrrk2 诱导的神经变性。