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：
7446650
负责人：
Darren John Moore
金额：
$ 21.53万
依托单位：
JOHNS HOPKINS UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/7446650
关键词：
Affect Alpha-Synuclein Conditional Knock-in Alpha-Synuclein transgenic mouse Brain Stem Breeding Chronic Clinical Development Disease Disease Progression Disease model Exhibits Family Functional disorder Gene Mutation Gene Targeting Generations Genes Genomics Half-Life Human Knock-in Mouse Lewy Bodies Methods Missense Mutation Modeling Motor Neurons Mus Muscle Rigidity Mutation Nerve Degeneration Neurons Parkinson Disease Parkinsonian Disorders Pathogenesis Pattern Pharmaceutical Preparations Phenotype Play Population Property Proteins Role SNCA gene Spinal Cord Substantia nigra structure Symptoms Testing Tissues Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Tremor Tyrosine Tyrosine 3-Monooxygenase Variant abstracting alpha synuclein base cell type cost dopaminergic neuron gain of function in vivo innovation mouse model mouse synuclein alpha mutant nervous system disorder neuromelanin neuropathology nigrostriatal dopaminergic pathway nigrostriatal pathway novel promoter protein expression recombinase selective expression synuclein, alpha (non A4 component of amyloid precursor) protein, human tool transgene expression

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-突触核蛋白有条件的敲入小鼠是帕金森氏病的新型模型抽象突变，在α-核蛋白基因中明确引起家族性帕金森氏病（PD）的罕见常染色体占主导地位显性形式。 α-核蛋白被认为是基于错义突变或三角核蛋白基因与家族性帕金森氏病的关系的关联或一式三份的相关性，并鉴定出alpha-synuclein的纤维化形式，是alpha-synuclein作为parkinson parkinson的大型结构性成分，并确定了alpha-synuclein的纤维化形式，在帕金森氏病的发病机构中起着核心作用。 α-突触核蛋白的家族突变通过有毒的功能获取机制引起帕金森氏病。通过以神经元特异性方式以神经元甲核素表达人α-核蛋白的致病变异的转基因小鼠模型，已经提供了功能获取机制的证据。这些转基因模型表现出室内功能障碍，选择性神经元变性的组合以及类似Lewy身体的细胞内夹杂物的形成。然而，黑质中的多巴胺能神经元令人惊讶地却一贯幸免。重要的是，由于明显缺乏黑质纹状体多巴胺能变性，目前的α-核蛋白转基因小鼠不提供帕金森氏病的强大模型，但可以代表有用的α-核核疾病模型。在α-突触核蛋白小鼠中缺乏强大的PD样表型可能与用于转基因表达的启动子的选择有关，因为其中许多倾向于在脑干和导致运动神经元相关的表型而非Nigrostriatialtriatiartialtriatal Pathway pathway-trophway photway-Inledecty phactotypepe的脑干和脊髓中驱动稳健的转基因表达。因此，α-突触核蛋白致病性变体的稳健转基因表达专门在黑质纹状体多巴胺能神经元中克服了这一问题，并将有选择地靶向帕金森氏病中受影响的主要神经元。 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.这些小鼠将被评估为一种新颖的帕金森氏病强大模型。在某些家庭中，称为α-核蛋白的基因中的突变是帕金森氏病的罕见原因。了解这些遗传突变如何引起疾病可能允许开发旨在制止，减慢或逆转疾病进展的新型疗法。我们的研究旨在模拟小鼠中α-突变核蛋白突变形式的致病作用，以便准确地重现帕金森氏病的典型特征，以便我们可以更好地理解这种疾病，以便我们最终能够最终使用此类小鼠来测试新的疗法。