LRRK2 in Parkinson's Disease Neurodegeneration

LRRK2 在帕金森病神经变性中的作用

基本信息

批准号：
10546462
负责人：
Ian Martin
金额：
$ 34.38万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10546462
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 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 age related aged dopaminergic neuron fly genome wide association study human data in vivo insight lifetime risk mRNA Translation motor deficit neurite growth neuron loss neurotoxicity novel overexpression technological innovation therapeutic development therapeutic target transcription factor

项目摘要

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.

项目概要预计到 2040 年，帕金森病 (PD) 的患病率将翻一番，但目前尚无治疗方法富含亮氨酸重复激酶 2 (LRRK2) 的广泛作用可延缓或阻止疾病进展。家族性和特发性帕金森病的突变已经出现，最终将其地位提升为核心疾病目标。预防 LRRK2 神经毒性需要详细了解驱动的关键机制与常见 LRRK2 G2019S 相关的最常见的神经元缺陷之一。体外突变是神经突长度和复杂性的损失，然而，这些缺陷在体内的性质及其不同。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。了解疾病病因的障碍。对 LRRK2 G2019S 遗传修饰物的公正筛选。神经退行性疾病导致了三个基因的发现：prospero、cut 和 pbl，它们都在神经突中发挥作用。这产生了繁荣、削减和 pbl 驱动 LRRK2 G2019S- 的假设。诱导多巴胺能神经突缺陷，并且这些缺陷对于多巴胺是必要和充分的在拟议的研究中，LRRK2 G2019S 对多巴胺能神经突的影响。果蝇在衰老过程中的生长和维持将通过条件转基因来确定过度表达 LRRK2 G2019S 将在整个生命周期中诱导表达。仅限于发育或衰老，以确定这如何影响观察到的多巴胺能神经突缺陷 LRRK2 G2019S 神经突缺陷中涉及 prospero、cut 和 pbl 的机制。将检查哺乳动物的细胞骨架调节及其在神经元死亡中的作用。 prospero (PROX1)、cut (CUX1) 和 pbl (ECT2) 与黑质多巴胺神经元损失的直向同源物将是在大鼠腺病毒模型中评估 LRRK2 G2019S 诱导的神经变性。拟议的研究将有助于理解 (i) LRRK2 G2019S- 的分子机制体内诱导神经突缺陷 (ii) 体内这些缺陷在发育和衰老过程中的性质 (iii) 这些缺陷对于与年龄相关的多巴胺神经元死亡是否是必要和充分的，以及（iv）是否已鉴定修饰物的哺乳动物直系同源物也导致 LRRK2 G2019S 神经变性。预计贡献将是巨大的，因为它将在理解驱动 PD 中 LRRK2 G2019S 神经变性的机制该提案包含了许多机制。概念和技术创新，实现对LRRK2-性质和机制的详细研究相关的神经突缺陷、它们在衰老过程中的动态及其与已建立的 PD 相关的联系表型。