LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease

帕金森病神经变性的 LRRK2 酶机制

基本信息

  • 批准号:
    10534730
  • 负责人:
  • 金额:
    $ 47.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-12-01 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused primarily by the degeneration of dopaminergic neurons in the substantia nigra. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant PD, and LRRK2 coding and non-coding variants are associated with risk of sporadic PD. LRRK2 has emerged has an important therapeutic target for treating PD and therefore it is critical to understand the key mechanisms underlying disease-linked mutations. LRRK2 is a large multi-domain protein containing Ras-of-Complex (Roc) GTPase and protein kinase enzymatic domains separated by a C-terminal-of-Roc (COR) domain. GTP-binding via the Roc domain is critical for normal kinase activity. Familial LRRK2 mutations cluster within the Roc (R1441C/G/H), COR (Y1699C) and kinase (G2019S, I2020T) domains where they commonly enhance the phosphorylation of a subset of Rab GTPase substrates in cells. Roc-COR domain mutations act indirectly on kinase activity by impairing GTP hydrolysis and promoting the GTP-bound `on' state. The GTPase and kinase domains represent promising targets for inhibiting LRRK2. While familial LRRK2 mutations share the capacity to induce neuronal damage in cultured cells, their effects in animal models are less certain due to a lack of robust neurodegenerative phenotypes. In addition, how the two enzymatic activities contribute to neuronal damage in vivo induced by familial LRRK2 mutations is poorly understood. We have recently developed an adenoviral-mediated gene transfer model in adult rats where G2019S LRRK2 induces nigrostriatal pathway dopaminergic neurodegeneration through a kinase-dependent mechanism. In the present application, we propose to exploit this robust and rapid rodent model to determine whether kinase activity is commonly required for neurodegeneration induced by familial mutations (R1441C, Y1699C and G2019S) or PD risk variants (G2385R) in LRRK2 by genetic and pharmacological kinase inhibition (Aim 1.1). The contribution of Rab phosphorylation to neuronal damage induced by mutant LRRK2 is not known. We will determine the neuroprotective effects of globally reducing Rab phosphorylation in mutant LRRK2 neuronal and adenoviral rat models by overexpressing a novel Rab-specific phosphatase, PPM1H (Aim 1.2). Knockdown of PPM1H will explore whether increasing Rab phosphorylation is sufficient to phenocopy the neurotoxic effects of mutant LRRK2. Our studies will further explore whether genetically modulating GTPase activity can provide a common neuroprotective mechanism against different familial LRRK2 mutations in rodents (Aim 2.1). In particular, we will evaluate hypothesis-testing mutations that increase GTP hydrolysis and promote the GDP-bound `off' state of LRRK2. Finally, we will explore how the native interactome of LRRK2 in neurons is regulated by the GTPase cycle to identify novel protein targets that interact with LRRK2 in its GDP- or GTP- bound states (Aim 2.2). Our studies will provide critical mechanistic insight into how GTPase and kinase activity regulate LRRK2-mediated neurodegeneration, and will be important for therapeutic discovery efforts for PD.
项目摘要 帕金森病(PD)是一种进行性神经退行性运动障碍,主要由 黑质内多巴胺能神经元变性。富含亮氨酸的重复蛋白激酶2的突变 (LRRK2)基因导致晚发型、常染色体显性帕金森病,而LRRK2编码和非编码变异体 与散发性帕金森病的风险相关。LRRK2已成为治疗帕金森病的重要靶点 因此,了解与疾病相关的突变背后的关键机制至关重要。LRRK2是一种 含Ras-of-Complex(Ras-of-Complex)GTP酶和蛋白激酶酶结构域的大分子多域蛋白 由C-末端的ROC(COR)结构域分隔。通过ROC结构域的GTP结合对正常的激酶是至关重要的 活动。家族性LRRK2突变位于ROC(R1441C/G/H)、COR(Y1699C)和KINK(G2019S, I2020T)结构域,它们通常增强Rab GTP酶底物子集的磷酸化。 细胞。ROC-COR结构域突变通过抑制GTP的水解和促进间接作用于激酶活性 与GTP绑定的“开”状态。GTPase和KK结构域是抑制LRRK2的有希望的靶点。 虽然家族性LRRK2突变具有诱导培养细胞神经元损伤的能力,但它们在 由于缺乏强大的神经退行性表型,动物模型不太确定。另外,两个人是如何 家族性LRRK2基因突变导致体内神经元损伤的酶活性很低 明白了。我们最近开发了一种腺病毒介导的成年大鼠基因转移模型, G2019S LRRK2通过激酶依赖性诱导黑质纹状体通路多巴胺能神经元变性 机制。在目前的应用中,我们建议利用这种健壮和快速的啮齿动物模型来确定 家族性突变引起的神经变性是否通常需要激酶活性(R1441C, LRRK2中的Y1699C和G2019S)或PD风险变异(G2385R)通过遗传和药理学的激酶抑制 (目标1.1)。Rab磷酸化在突变型LRRK2诱导的神经元损伤中的作用尚不清楚。 我们将确定全局减少突变型LRRK2中Rab磷酸化的神经保护作用 通过过表达一种新的Rab特异性磷酸酶PPM1H来建立神经元和腺病毒大鼠模型(Aim 1.2)。 PPM1H的敲除将探索增加Rab磷酸化是否足以复制表型 突变体LRRK2的神经毒性作用。我们的研究将进一步探索基因调控GTP酶 在啮齿动物中,活性可以为不同家族性LRRK2突变提供共同的神经保护机制 (目标2.1)。特别是,我们将评估假设检验突变,这些突变增加GTP水解度并促进 LRRK2与国内生产总值有关的“关闭”状态。最后,我们将探索LRRK2在神经元中的天然相互作用组是如何 受GTPase循环调节,以确定与GDP-或GTP-LRRK2相互作用的新蛋白质靶点 束缚态(目标2.2)。我们的研究将提供关键的机制洞察GTP酶和激酶的活性 调节LRRK2介导的神经退行性变,对于帕金森病的治疗发现工作将是重要的。

项目成果

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Darren John Moore其他文献

Darren John Moore的其他文献

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{{ truncateString('Darren John Moore', 18)}}的其他基金

Exploring mechanisms of Parkinson's disease-linked D620N VPS35 in rat models
在大鼠模型中探索帕金森病相关 D620N VPS35 的机制
  • 批准号:
    10445271
  • 财政年份:
    2020
  • 资助金额:
    $ 47.5万
  • 项目类别:
Exploring mechanisms of Parkinson's disease-linked D620N VPS35 in rat models
在大鼠模型中探索帕金森病相关 D620N VPS35 的机制
  • 批准号:
    10202777
  • 财政年份:
    2020
  • 资助金额:
    $ 47.5万
  • 项目类别:
LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease
帕金森病神经变性的 LRRK2 酶机制
  • 批准号:
    10306405
  • 财政年份:
    2020
  • 资助金额:
    $ 47.5万
  • 项目类别:
Exploring mechanisms of Parkinson's disease-linked D620N VPS35 in rat models
在大鼠模型中探索帕金森病相关 D620N VPS35 的机制
  • 批准号:
    10656398
  • 财政年份:
    2020
  • 资助金额:
    $ 47.5万
  • 项目类别:
Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 VPS35 依赖性神经变性的机制
  • 批准号:
    9753383
  • 财政年份:
    2017
  • 资助金额:
    $ 47.5万
  • 项目类别:
Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 VPS35 依赖性神经变性的机制
  • 批准号:
    9975928
  • 财政年份:
    2017
  • 资助金额:
    $ 47.5万
  • 项目类别:
Linking Synucleinopathy and Dysfunction of Olfactory Pathways
突触核蛋白病和嗅觉通路功能障碍之间的联系
  • 批准号:
    10183218
  • 财政年份:
    2017
  • 资助金额:
    $ 47.5万
  • 项目类别:
Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 VPS35 依赖性神经变性的机制
  • 批准号:
    10227170
  • 财政年份:
    2017
  • 资助金额:
    $ 47.5万
  • 项目类别:
Novel Mechanisms of LRRK2-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 LRRK2 依赖性神经变性的新机制
  • 批准号:
    9329506
  • 财政年份:
    2015
  • 资助金额:
    $ 47.5万
  • 项目类别:
Novel Mechanisms of LRRK2-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 LRRK2 依赖性神经变性的新机制
  • 批准号:
    9763678
  • 财政年份:
    2015
  • 资助金额:
    $ 47.5万
  • 项目类别:

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