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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.

帕金森病（PD）是最常见的神经退行性疾病之一，其特点是选择性的