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Targeting proteostatic mechanisms to inhibit LRRK2-mediated neurodegeneration and neuropathology

Targeting proteostatic mechanisms to inhibit LRRK2-mediated neurodegeneration and neuropathology
靶向蛋白抑制机制抑制 LRRK2 介导的神经变性和神经病理学
批准号:
10807879
负责人:
Annie E Hiniker
金额:
$64.86万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-21 至 2028-08-31

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中文摘要
翻译
神经退行性痴呆,如阿尔茨海默病(AD)、额颞叶 退行性变和路易体痴呆是由蛋白质平衡异常和 错误折叠的类病毒蛋白在大脑中的堆积。富含亮氨酸重复序列的突变 蛋白激酶2(LRRK2)基因可导致多种神经病理改变,包括肌萎缩侧索硬化症、突触核病、 TDP-43蛋白病变与AD病理的关系。携带LRRK2突变的患者经常发生 临床痴呆,近一半LRRK2驱动的神经退行性变患者发生tau 或其他病理改变,而不是联核症。因此,LRRK2是一个关键的调节器,控制 蛋白质聚集和神经退行性变,并确定LRRK2的机制 突变驱动了这种不同的普恩病毒样病理,可能会导致新的靶向治疗。这个 拟议的研究旨在表征蛋白的上游和下游的机制 使用LRRK2患者来源的神经元和罕见的死后LRRK2患者脑组织。这个 研究有三个目标。首先,明确LRRK2‘S的亚细胞定位在其细胞内的作用 功能和降解,特别关注LRRK2微管结合和 内溶酶体激活。第二,测试新发现的LRRK2蛋白在多大程度上 降解途径挽救患者衍生的衰老神经元和其他疾病的神经毒性 相关制度。第三,确定LRRK2突变可以驱动两者的机制 使用实时抖动诱导转换(RT-QuIC)的联核病和变态病,详细 一组罕见的LRRK2患者大脑的神经病理学和细胞类型特异性转录片段 纸巾。总体而言,这些研究应该开始定义LRRK2驱动的机制 并提供了对LRRK2作为治疗靶点的相关性的见解 用来治疗紧张症。
英文摘要
Neurodegenerative dementias, such as Alzheimer's disease (AD), frontotemporal lobar degeneration, and Lewy body dementia, are caused by abnormalities in proteostasis and accumulation of misfolded prion-like proteins in the brain. Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene result in diverse neuropathology, including tauopathy, synucleinopathy, TDP-43 proteinopathy, and AD pathology. Patients with LRRK2 mutations frequently develop clinical dementia, and nearly half of patients with LRRK2-driven neurodegeneration develop tau or other pathology instead of synucleinopathy. LRRK2 is therefore a key regulator controlling protein aggregation and neurodegeneration, and defining the mechanisms by which LRRK2 mutations drive such varied prion-like pathology may lead to novel targeted therapeutics. The proposed study aims to characterize the proteostatic mechanisms upstream and downstream of LRRK2 using patient-derived neurons and rare postmortem LRRK2 patient brain tissue. The study has three goals. First, to define the role of LRRK2’s subcellular localization in its cellular functions and degradation, with a particular focus on LRRK2 microtubule association and endolysosomal activation. Second, to test the extent to which newly identified LRRK2 protein degradation pathways rescue neurotoxicity in patient-derived aged neurons and other disease relevant systems. Third, to define the mechanisms by which LRRK2 mutations can drive both synucleinopathy and tauopathy using real-time quaking-induced conversion (RT-QuIC), detailed neuropathology, and cell-type specific transcriptomics on a rare cohort of LRRK2 patient brain tissues. Overall, these studies should begin to define the mechanisms by which LRRK2 drives myriad neuropathology and provide insight into the relevance of LRRK2 as a therapeutic target for tauopathies.
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Chemical-Genetic Approaches to Define Lrrk2 Kinase Function in Parkinson Disease
Chemical-Genetic Approaches to Define Lrrk2 Kinase Function in Parkinson Disease
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