LRRK2 dimerization and therapeutic evaluation

帕金森病（Parkinson's disease，PD）是最常见的神经退行性疾病之一，其特征在于选择性的 多巴胺能神经元的损失和路易体的存在。目前，还没有被证实的神经保护 用于PD的治疗和用于鉴定新治疗的方法尚不发达。突变 富含亮氨酸重复序列激酶-2（LRRK2）是帕金森病（PD）最常见的已知病因。 LRRK2是一个大的胞质蛋白（2527 aa），并含有GT3和激酶活性。虽然 已经努力开发LRRK2靶向疗法，到目前为止，这些疗法都没有用于治疗。 临床设置。因此，在大LRRK2蛋白中探索和鉴定新的治疗位点可以 为PD干预提供新途径。最近的研究表明，LRRK 2 GTPase结构域在细胞内发挥着重要作用。 LRRK2功能的重要作用。GTP结构域内的PD连锁LRRK2突变改变GTP 结合或GTP酶活性。通过遗传改变或药物抑制消除GTP结合 减弱LRRK2激酶活性并防止神经变性。值得注意的是， LRRK2 GT3结构域显示它是一个二聚体，生物学研究表明LRRK2可能需要 二聚化以作为参与细胞过程和神经元生长的功能蛋白。在本提案中，我们 建议使用计算机辅助药物靶向LRRK2 GT3结构域并鉴定二聚化抑制剂 设计（CADD）和生物筛选。我们将检验这样的假设，即通过小分子抑制剂阻断LRRK2二聚化， 分子可以减弱LRRK2细胞和果蝇模型中LRRK2诱导的神经变性。这些 研究将验证阻断LRRK2 GT3结构域二聚化是否是一个可行的靶点， 开发用于PD干预的新型治疗剂，并为PD治疗提供新的药理学工具。 LRRK2相关的发病机制和治疗研究。

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.