Alpha-Synuclein Conditional Knock-in Mice as Novel Models of Parkinson's Disease

α-突触核蛋白条件敲入小鼠作为帕金森病的新模型

基本信息

  • 批准号:
    7313499
  • 负责人:
  • 金额:
    $ 17.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-07-01 至 2009-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Alpha-Synuclein Conditional Knock-in Mice as Novel Models of Parkinson's Disease Abstract Mutations in the alpha-synuclein gene unequivocally cause rare autosomal dominant forms of familial Parkinson's disease (PD). Alpha-synuclein is considered to play a central role in the pathogenesis of Parkinson's disease based upon the association of missense mutations or triplications of the alpha- synuclein gene with familial Parkinson's disease, as well as the identification of fibrillar forms of alpha-synuclein as a major structural component of Lewy bodies in Parkinson's disease and other alpha-synucleinopathies. Familial mutations in alpha-synuclein cause Parkinson's disease through a toxic gain-of-function mechanism. Evidence for a gain-of-function mechanism has been provided through the generation of transgenic mouse models of Parkinson's disease that express pathogenic variants of human alpha-synuclein in a neuronal-specific manner. These transgenic models exhibit combinations of motoric dysfunction, selective neuronal degeneration, and the formation of intracellular inclusions resembling Lewy bodies. However, dopaminergic neurons in the substantia nigra are surprisingly yet consistently spared. Importantly, current alpha-synuclein transgenic mice do not provide a robust model of Parkinson's disease due to the conspicuous absence of nigrostriatal dopaminergic degeneration but may instead represent useful alpha-synucleinopathy models. The lack of a robust PD-like phenotype in alpha-synuclein mice may relate to the choice of promoter employed for transgene expression, since many of these tend to drive robust transgene expression within the brainstem and spinal cord of mice leading to motor neuron-related phenotypes rather than nigrostriatal pathway-related phenotypes. Thus, robust transgenic expression of alpha-synuclein pathogenic variants specifically within nigrostriatal dopaminergic neurons would overcome this problem and would selectively target the principal neurons affected in Parkinson's disease. To achieve expression of alpha-synuclein pathogenic variants within nigrostriatal dopaminergic neurons, a conditional Cre-loxP-based knock-in strategy will be employed to generate mice that express alpha-synuclein variants (wild-type and E46K mutant) specifically within tyrosine hydroxylase (TH)-positive catecholaminergic neurons. These mice will be evaluated as a novel, robust model of Parkinson's disease. Mutations in a gene called alpha-synuclein are a rare cause of Parkinson's disease in some families. Understanding how these genetic mutations cause disease may allow the development of novel therapies aimed at halting, slowing or reversing disease progression. Our studies aim to model the pathogenic effects of mutant forms of alpha-synuclein in mice in order to accurately recreate the typical features of Parkinson's disease so that we can better understand this disease, and so that we may be able to ultimately use such mice to test novel therapies.
描述(由申请人提供):α-突触核蛋白条件敲入小鼠作为帕金森病的新模型 摘要 α-突触核蛋白基因突变明确导致罕见的常染色体显性形式的家族性帕金森病(PD)。基于α-突触核蛋白基因的错义突变或三倍体与家族性帕金森病的关联,以及将纤维形式的α-突触核蛋白鉴定为帕金森病的发病机制,认为α-突触核蛋白在帕金森病的发病机制中发挥核心作用。帕金森病和其他 α-突触核蛋白病中路易体的主要结构成分。 α-突触核蛋白的家族突变通过毒性功能获得机制导致帕金森病。通过生成帕金森病转基因小鼠模型,提供了功能获得机制的证据,该模型以神经元特异性方式表达人类α-突触核蛋白的致病性变异。这些转基因模型表现出运动功能障碍、选择性神经元变性和类似路易体的细胞内包涵体形成的组合。然而,令人惊讶的是,黑质中的多巴胺能神经元却始终幸免于难。重要的是,目前的α-突触核蛋白转基因小鼠由于明显缺乏黑质纹状体多巴胺能变性而不能提供稳健的帕金森病模型,但可能代表有用的α-突触核蛋白病模型。 α-突触核蛋白小鼠中缺乏稳健的 PD 样表型可能与用于转基因表达的启动子的选择有关,因为其中许多启动子往往会在小鼠的脑干和脊髓内驱动稳健的转基因表达,从而导致运动神经元相关的表型而不是黑质纹状体途径相关的表型。因此,特异地在黑质纹状体多巴胺能神经元内α-突触核蛋白致病性变异的稳健转基因表达将克服这个问题,并选择性地靶向帕金森病受影响的主要神经元。为了实现黑质纹状体多巴胺能神经元内α-突触核蛋白致病性变异的表达,将采用基于Cre-loxP的条件敲入策略来产生在酪氨酸羟化酶内特异表达α-突触核蛋白变异体(野生型和E46K突变体)的小鼠。 TH)-阳性儿茶酚胺能神经元。这些小鼠将被评估为一种新型、稳健的帕金森病模型。 α-突触核蛋白基因突变是某些家族帕金森病的罕见原因。了解这些基因突变如何导致疾病可能有助于开发旨在阻止、减缓或逆转疾病进展的新疗法。我们的研究旨在模拟α-突触核蛋白突变体对小鼠的致病作用,以便准确地重现帕金森病的典型特征,以便我们能够更好地了解这种疾病,并最终能够利用这些小鼠来治疗帕金森病。测试新疗法。

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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    10534730
  • 财政年份:
    2020
  • 资助金额:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 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:
    $ 17.94万
  • 项目类别:

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Molecular, cellular and physiological mechanisms of the mammalian circadian clock
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  • 批准号:
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  • 财政年份:
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Alpha-Synuclein Conditional Knock-in Mice as Novel Models of Parkinson's Disease
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