Behavioral and Neuroanatomical Characterization of a Novel Genetic Animal Model o

描述（由申请方提供）：编码溶酶体P型ATP酶的ATP 13 A2突变导致KuforRakeb综合征，这是帕金森病（PD）的一种非典型形式。它的酵母直系同源物YPK 9也已被证明可以防止α-突触核蛋白和锰诱导的毒性，分别建立了PD的遗传和环境风险因素。这些观察结果表明，ATP 13 A2可能在PD发病机制中发挥重要作用，可能是通过其对溶酶体蛋白降解途径（自噬）的影响和/或通过螯合锰的功能，防止其神经毒性作用。我们通过破坏小鼠Atp 13 a2基因，建立了这种罕见的家族性PD的动物模型。在目标1中，我们将描述基因敲除小鼠的特征，以确定它们是否表现出PD的任何行为或神经解剖学特征，如运动功能障碍和黑质纹状体通路中多巴胺能神经元的丢失。为了实现这一目标，野生型（Atp 13 a2 +/+）和Atp 13 a2缺陷型（Atp 13 a2-/-）小鼠将接受一系列行为测定，以评估运动功能、学习和记忆，并进行组织学分析，以确定脑神经解剖学的改变，重点是黑质（SN）和苍白球（GP），这两个区域已知分别在散发性PD和KuforRakeb综合征中受到影响。在目标2中，我们将评估Atp 13 a2-/-小鼠和来源于它们的原代中脑培养物对锰的敏感性，我们预计这可能会加剧它们相对于对照的表型。如目标1所述，将对长期暴露于锰的小鼠进行行为和组织学分析，同时进行细胞活力和免疫细胞化学测定以及氧化应激测量，以评估原代中脑培养物中神经元对锰毒性作用的敏感性。从这些研究中获得的数据可能有助于建立PD遗传和环境风险因素之间的重要联系，并提高我们对散发性和遗传性PD的病理机制的理解。 公共卫生相关性：帕金森病（PD）是第二大最常见的神经退行性疾病。我们已经建立了一个小鼠动物模型来研究这种罕见的遗传性疾病，称为库福-雷凯布综合征。我们的发现可能会导致对PD及其治疗的原因的新见解。

DESCRIPTION (provided by applicant): Mutations in ATP13A2, which encodes a lysosomal P type ATPase, result in KuforRakeb syndrome, an atypical form of Parkinson's disease (PD). Its yeast ortholog, YPK9, has also been shown to protect against a-synuclein and manganese-induced toxicity, established genetic and environmental risk factors for PD, respectively. These observations suggest that ATP13A2 may play an important role in PD pathogenesis, possibly through its influence on lysosomal protein degradation pathways (autophagy) and/or by functioning to sequester manganese, protecting against its neurotoxic effects. We have established an animal model for this rare, familial form of PD by disrupting the Atp13a2 gene in mice. In Aim 1 we will characterize the knockout mice to determine if they exhibit any of the behavioral or neuroanatomical hallmarks of PD such as motor dysfunction and loss of dopaminergic neurons in the nigrostriatal pathway. To achieve this aim wildtype (Atp13a2+/+) and Atp13a2deficient (Atp13a2-/-) mice will be subjected to an array of behavioral assays to assess motor function, learning, and memory and histological analyses to identify alterations in brain neuroanatomy with emphasis placed on the substantia nigra (SN) and globus pallidus (GP), regions known to be affected in sporadic PD and KuforRakeb syndrome, respectively. In Aim 2 we will evaluate the sensitivity of the Atp13a2-/- mice and primary mesencephalic cultures derived from them to manganese, which we anticipate may exacerbate their phenotype relative to controls. Behavioral and histological analyses on mice chronically exposed to manganese will be carried out as described in Aim 1, while cell viability and immunocytochemical assays and measurements of oxidative stress will be performed to assess the sensitivity of neurons in the primary mesencephalic cultures to the toxic effects of manganese. Data obtained from these studies may help establish an important link between genetic and environmental risk factors for PD and improve our understanding of the pathological mechanisms underlying both sporadic and genetic forms of PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have created a mouse animal model to research a rare, inherited form of this disease called Kufor- Rakeb syndrome. Our findings could lead to new insights into the causes of PD and its treatment.