LRRK2 in Parkinson's Disease Neurodegeneration

LRRK2 在帕金森病神经变性中的作用

• 批准号: 10363330
• 负责人: Ian Martin
• 金额: $ 35.73万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363330
• 关键词: Adult; Affect; Age; Aging; Animals; Automobile Driving; Biological Assay; Brain Diseases; Cytoskeleton; Defect; Development; Disease; Disease Progression; Drosophila genus; Environmental Risk Factor; Etiology; F-Actin; Functional disorder; Future; Gene Silencing; Genes; Genetic; Genetic Screening; Genetic Translation; Goals; Human; Idiopathic Parkinson Disease; In Vitro; LRRK2 gene; Lead; Length; Longevity; Maintenance; Measures; Mediating; Microtubules; Modeling; Molecular; Morphology; Mutation; Nature; Nerve Degeneration; Neurites; Neurons; Orthologous Gene; Parkinson Disease; Persons; Phenotype; Phosphotransferases; Prevalence; Prevention; Rattus; Regulation; Research; Role; Substantia nigra structure; Testing; Therapeutic; Transgenic Organisms; age related; aged; dopaminergic neuron; fly; genome wide association study; human data; in vivo; insight; lifetime risk; motor deficit; neurite growth; neuron loss; neurotoxicity; novel; overexpression; technological innovation; therapeutic development; therapeutic target; transcription factor

PROJECT SUMMARY Parkinson’s disease (PD) is projected to double in prevalence by 2040 and yet there are no current therapeutic approaches that delay or stop disease progression. A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged, elevating its status to a central disease target. Ultimately, prevention of LRRK2 neurotoxicity will require a detailed understanding of the key mechanisms driving neurodegeneration. One of the most frequent neuronal defects associated with the common LRRK2 G2019S mutation in vitro is a loss of neurite length and complexity. Yet, the nature of these defects in vivo, their underlying cause, and their relationship to dopamine neuron death are all unknown. This creates a major roadblock to understanding disease etiology. An unbiased screen for genetic modifiers of LRRK2 G2019S neurodegeneration lead to the discovery of three genes; prospero, cut and pbl, which all have roles in neurite outgrowth and maintenance. This generates the hypothesis that prospero, cut and pbl drive LRRK2 G2019S- induced dopaminergic neurite defects, and that these defects are necessary and sufficient for dopamine neuron death in aged animals. In the proposed studies, the impact of LRRK2 G2019S on dopaminergic neurite growth and maintenance across aging in Drosophila will be determined using conditional transgenics that overexpress LRRK2 G2019S. LRRK2 G2019S expression will be induced either throughout the life span or restricted to development or aging to determine how this impacts dopaminergic neurite defects observed in aged flies. Mechanisms involving prospero, cut and pbl in LRRK2 G2019S neurite defects through altered cytoskeletal regulation and their role in neuronal death will be examined. The contribution of the mammalian orthologs of prospero (PROX1), cut (CUX1) and pbl (ECT2) to substantia nigra dopamine neuron loss will be assessed in a rat adenoviral model of LRRK2 G2019S-induced neurodegeneration. Successful completion of the proposed research will contribute to the understanding of (i) molecular mechanisms of LRRK2 G2019S- induced neurite defects in vivo (ii) the nature of these defects across development and aging in vivo (iii) whether these defects are necessary and sufficient for age-related dopamine neuron death and (iv) whether the mammalian orthologs of the identified modifiers also contribute to LRRK2 G2019S neurodegeneration. This contribution is expected to be significant because it will provide a major advance in understanding the mechanisms driving LRRK2 G2019S neurodegeneration in PD. This proposal incorporates a number of conceptual and technological innovations to achieve a detailed study of the nature and mechanisms of LRRK2- related neurite defects, their dynamics across aging and their connection to established PD-related phenotypes.

项目总结 帕金森氏病(PD)的患病率预计到2040年将翻一番，但目前还没有治疗方法 延缓或阻止疾病进展的方法。富含亮氨酸的重复蛋白激酶2(LRRK2)的广泛作用 家族性和特发性帕金森病的突变已经出现，将其地位提升到中心疾病靶点。最终， 预防LRRK2神经毒性需要详细了解驱动的关键机制 神经退行性变。与常见的LRRK2 G2019S相关的最常见的神经元缺陷之一 体外突变是一种丧失轴突长度和复杂性的现象。然而，这些体内缺陷的性质，他们的 根本原因，以及它们与多巴胺神经元死亡的关系都是未知的。这创造了一个重大的 这是理解疾病病因的障碍。LRRK2 G2019S基因修饰物的无偏筛选 神经退行性变导致了三个基因的发现：propero、Cut和PBL，它们都在轴突中发挥作用 成长和维护。这就产生了这样的假设：Propero、Cut和PBL驱动LRRK2 G2019S- 诱导的多巴胺能神经突起缺陷，这些缺陷是多巴胺的必要条件和充分条件 老年动物的神经元死亡。在拟议的研究中，LRRK2 G2019S对多巴胺能神经突起的影响 果蝇在衰老过程中的生长和维持将使用条件转基因来确定 过表达LRRK2 G2019S。LRRK2 G2019S的表达将在整个生命周期或 仅限于发育或老化，以确定这如何影响观察到的多巴胺能轴突缺陷 苍蝇老了。LRRK2 G2019S轴突变性损伤中Propero、Cut和PBL的作用机制 本课程将研究细胞骨架调节及其在神经元死亡中的作用。哺乳动物的贡献 Propero(PROX1)、CuT(CUX1)和PBL(ECT2)的同源基因将导致黑质多巴胺神经元丢失 在LRRK2 G2019S诱导的神经变性的大鼠腺病毒模型中进行评估。成功完成 本研究将有助于理解LRRK2 G2019S的分子机制。 体内诱导的轴突缺陷(II)体内发育和衰老过程中这些缺陷的性质(III) 这些缺陷对于年龄相关的多巴胺神经元死亡是否必要且充分；以及(Iv) 已鉴定修饰物的哺乳动物同源基因也与LRRK2 G2019S神经变性有关。这 预计这一贡献将是巨大的，因为它将在理解 帕金森病患者LRRK2 G2019S神经退行性变的机制这项建议包含了一些 概念和技术创新，以实现对LRRK2性质和机制的详细研究- 相关轴突缺陷、其随年龄增长的动态变化及其与已建立的帕金森病相关关系 表型。