Targeting proteostatic mechanisms to inhibit LRRK2-mediated neurodegeneration and neuropathology

神经退行性痴呆，如阿尔茨海默病（AD）、额颞叶痴呆、阿尔茨海默病和阿尔茨海默病。 变性和路易体痴呆是由蛋白质稳态异常引起的， 大脑中错误折叠的朊病毒样蛋白的积累。富含亮氨酸重复序列中的突变 激酶2（LRRK 2）基因导致多种神经病理学，包括tau蛋白病、突触核蛋白病 TDP-43蛋白质病和AD病理学。LRRK 2突变的患者经常发生 临床痴呆，近一半的LRRK 2驱动的神经退行性疾病患者发展tau蛋白 或其他病理学而不是突触核蛋白病。因此，LRRK 2是一个关键的调节器， 蛋白质聚集和神经变性，并确定LRRK 2 突变驱动这种不同的朊病毒样病理可能导致新的靶向治疗。的 拟议的研究旨在表征蛋白质上游和下游的蛋白质抑制机制， LRRK 2使用患者来源的神经元和罕见的死后LRRK 2患者脑组织。的 研究有三个目标。首先，为了明确LRRK 2的亚细胞定位在其细胞内的作用， 功能和降解，特别关注LRRK 2微管缔合， 内溶酶体激活第二，为了测试新鉴定的LRRK 2蛋白在多大程度上 降解途径挽救患者来源的老化神经元中的神经毒性和其他疾病 相关制度。第三，确定LRRK 2突变可以驱动两种机制的机制。 突触核蛋白病和tau蛋白病使用实时震动诱导转换（RT-QuIC），详细 神经病理学和细胞类型特异性转录组学对罕见的LRRK 2患者脑的队列研究 组织中总的来说，这些研究应该开始定义LRRK 2驱动的机制。 并提供了对LRRK 2作为治疗靶点的相关性的见解 治疗tau蛋白病

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.