LRRK2 dimerization and therapeutic evaluation

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 多巴胺能神经元的丢失和路易小体的存在。目前，还没有得到证实的神经保护措施。 帕金森病的治疗方法和确定新治疗方法的方法还不够发达。基因突变 富含亮氨酸的重复蛋白-2(LRRK2)是帕金森病(PD)最常见的致病原因。 LRRK2是一个大的胞质蛋白(2527aa)，具有GTP酶和激酶活性。虽然 已经在开发LRRK2靶向疗法上花费了努力，到目前为止，这些疗法都没有被用于 临床环境。因此，探索和鉴定大分子LRRK2蛋白中的新的治疗位点(S)可能 为帕金森病干预提供新的途径。最近的研究表明，LRRK2 GTP酶结构域在 在LRRK2功能中发挥重要作用。GTP酶结构域内PD连锁的LRRK2突变改变GTP中的任何一个 结合或GTP酶活性。通过基因改变或药物抑制取消GTP结合 减弱LRRK2激酶活性，防止神经退行性变。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 二聚体作为一种功能蛋白参与细胞过程和神经元生长。在这项提案中，我们 建议使用计算机辅助药物靶向LRRK2 GTPase结构域并识别二聚抑制物 设计(CADD)和生物筛选。我们将检验通过小分子阻断LRRK2二聚化的假设 分子可减轻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 GTPase结构域二聚是否是一个可行的目标 开发用于PD干预的新型治疗剂，并提供新的药理工具 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.