LRRK2 dimerization and therapeutic evaluation

LRRK2二聚化和治疗评估

基本信息

批准号：
9352885
负责人：
WANLI W SMITH
金额：
$ 24.02万
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：
2016-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352885
关键词：
Affect Age Attenuated Biochemical Biological Brain Cell physiology Cells Chemicals Clinical Computer Assisted Computer Simulation Crystallization Cytoplasmic Protein Deposition Development Dimerization Disease Disease Progression Drosophila genus Drug Design Event Future GTP Binding Goals Guanosine Triphosphate Phosphohydrolases Homologous Gene Human In Vitro Intervention LRRK2 gene Lead Lewy Bodies Link Modality Modeling Molecular Molecular Weight Mutation Nerve Degeneration Neurodegenerative Disorders Parkinson Disease Pathogenesis Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphotransferases Pilot Projects Play Population Proteins Reporting Research Roentgen Rays Role Site Structure Structure-Activity Relationship Substantia nigra structure Symptoms Testing Therapeutic Agents Therapeutic Intervention Therapeutic Studies Toxic effect base dimer dopaminergic neuron drug development drug discovery in vivo inhibitor/antagonist insight kinase inhibitor motor symptom mutant neuron loss neuronal growth new therapeutic target novel novel therapeutic intervention novel therapeutics prevent small molecule symptom treatment targeted treatment therapeutic evaluation tool

项目摘要

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Currently, there is no proven neuroprotective therapy for PD and approaches for the identification of novel treatments are underdeveloped. Mutations in Leucine-rich repeat kinase-2 (LRRK2) are the most common known cause of Parkinson's disease (PD). LRRK2 is a large cytoplasmic protein (2527 aa) and contains both GTPase and kinase activities. Although efforts have been spent on developing LRRK2-targeted therapies, so far none of these are being utilized in a clinical setting. Thus, exploration and identification of novel therapeutic site(s) in the large LRRK2 protein may provide novel avenues for PD intervention. Recent studies suggest that the LRRK2 GTPase domain plays an important role in LRRK2 functions. PD-linked LRRK2 mutations within the GTPase domain alter either GTP binding or GTPase activity. Abolishing GTP binding by genetic alteration or pharmacological inhibition attenuates LRRK2 kinase activity and protects against neurodegeneration. Notably, the crystal structure of the LRRK2 GTPase domain shows it to be a dimer and biological studies suggest that LRRK2 may need to dimerize to act as a functional protein involved in cellular processes and neuronal growth. In this proposal, we propose to target the LRRK2 GTPase domain and identify dimerization inhibitors using computer-aided drug design (CADD) and biological screens. We will test the hypothesis that blocking LRRK2 dimerization by small molecules can attenuate LRRK2-induced neurodegeneration in LRRK2 cell and Drosophila models. These studies will validate whether blocking LRRK2 GTPase domain dimerization is a viable target for the development of novel therapeutic agents for PD intervention, and provide novel pharmacological tools for LRRK2-linked pathogenesis and therapeutic studies.

帕金森氏病（PD）是最常见的神经退行性疾病之一，其特征是选择性多巴胺能神经元的丧失和路易体的存在。目前，没有经过证实的神经保护 PD的治疗和鉴定新疗法的方法欠发达。突变富含亮氨酸的重复激酶2（LRRK2）是帕金森氏病（PD）的最常见原因。 LRRK2是一种大的细胞质蛋白（2527 AA），并包含GTPase和激酶活性。虽然已经花在开发LRRK2靶向疗法上了临床环境。因此，大型LRRK2蛋白中新型治疗部位的探索和鉴定可能为PD干预提供新的途径。最近的研究表明，LRRK2 GTPase结构域发挥 LRRK2函数中的重要作用。 GTPase结构域内的PD连接LRRK2突变改变了任一GTP 结合或GTPase活性。通过遗传改变或药理抑制来消除GTP结合减弱LRRK2激酶活性并预防神经变性。值得注意的是， LRRK2 GTPase结构域表明它是一个二聚体，生物学研究表明LRRK2可能需要二聚体充当参与细胞过程和神经元生长的功能蛋白。在这个建议中，我们建议针对LRRK2 GTPase域并使用计算机辅助药物识别二聚化抑制剂设计（CADD）和生物屏幕。我们将测试以下假设：通过小型阻止LRRK2二聚体分子可以减弱LRRK2诱导的LRRK2细胞和果蝇模型中的神经退行性。这些研究将验证阻断LRRK2 GTPase域二聚体是否是可行的目标开发用于PD干预的新型治疗剂，并为新颖的药理学工具提供 LRRK2连接的发病机理和治疗研究。