Detoxification of Biogeneic Aldehydes in Parkinson's Disease

生物醛在帕金森病中的解毒作用

• 批准号: 8440618
• 负责人: RANDY STRONG
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440618
• 关键词: 1-Methyl-4-phenylpyridinium; Accounting; Affect; Age; Aldehydes; Alzheimer' s Disease; Animals; Behavior; Behavioral; Biochemical; Biological Assay; Biological Markers; Brain; Cell Death; Clinical; Corpus striatum structure; Diagnostic; Disease; Disease Progression; Dopamine; Drug Metabolic Detoxication; Environmental Exposure; Epidemiologic Studies; Etiology; Excision; Exhibits; Exposure to; FDA approved; Family; Functional disorder; Funding; Gene Mutation; Genetic; Histopathology; Human; Hydralazine; Hydrophobicity; Impairment; Isoenzymes; Knockout Mice; Link; Maneb; Measurement; Measures; Midbrain structure; Military Personnel; Modeling; Motor; Movement; Mus; Muscle Rigidity; Mutation; Neurodegenerative Disorders; Neurotoxins; Paraquat; Parkinson Disease; Pathogenesis; Patients; Peripheral; Pesticides; Pharmaceutical Preparations; Phenotype; Population; Presynaptic Terminals; Process; Research; Rest Tremor; Risk; Role; Rotenone; Safety; Substantia nigra structure; Symptoms; Testing; Tissues; Toxic Environmental Substances; Toxin; Ubiquitin; Veterans; Wild Type Mouse; Work; adduct; age related; aged; aldehyde dehydrogenase 1; aldehyde dehydrogenases; alpha synuclein; dopaminergic neuron; environmental agent; neurochemistry; neuropathology; neuroprotection; neurotoxic; novel therapeutics; overexpression; preclinical study; prevent; protein aggregate; protein folding; public health relevance; synuclein; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder, after Alzheimer's disease, affecting up to 5% of the population aged 65 - 85 years the clinical manifestations of PD include slowness of voluntary movement, resting tremor, muscle rigidity and postural instability. The major biochemical abnormality is a profound loss of dopamine in the substantia nigra (SN) and striatum, resulting from loss of dopaminergic neurons in the substantia nigra and their axon terminals in the striatum. Other prominent pathological features include the presence of intraneuronal inclusions consisting of protein aggregates containing a-synuclein and ubiquitin. Despite great strides in research over the past two decades, the etiology and pathogenesis of the disease is still largely unknown. Although families have been identified with single gene mutations that cause PD-like symptoms, they account for a relatively small number of PD cases. The majority of PD cases are classified as idiopathic or of unknown cause. Human and animal studies have established a link between environmental exposure to paraquat, maneb and rotenone in idiopathic or sporadic PD. The mechanisms by which exposure to pesticides with different mechanisms of action may cause PD are not fully understood, and treatment strategies to prevent or slow disease progression have not been identified. However, a growing body of evidence from our lab and others has implicated impaired aldehyde detoxification. Our working hypothesis is that impaired aldehyde detoxification leads to elevated "aldehyde load" including increased levels of DOPAL and 4-HNE. These aldehydes or their metabolites can form adducts with a-synuclein, leading to formation of toxic fibrils and eventually cell death. To test the hypothesis that impaired aldehyde detoxification is mechanistically linked to dopaminergic dysfunction; we created two lines of mice, one with homozygous mutations in the two aldehyde dehydrogenase isozymes, Aldh1a1 and Aldh2, that are known to be present in midbrain dopamine neurons, and the other a line of wild- type mice from their littermates on the identical genetic background. We then examined the effects of Aldh1a1/Aldh2-deficiency on their behavioral and neurochemical phenotypes. Our results show that mice deficient in Aldh1a1/Aldh2 exhibit impairments in motor function that are reversed by L-DOPA, reduced dopamine and metabolites and loss of midbrain dopamine neurons. The overall aim is to test mechanistically determine how increased aldehyde load is connected to dopaminergic dysfunction and evaluate aldehydes as a therapeutic target. Our Specific Aims are: Aim 1: To determine whether impaired aldehyde detoxification increases the sensitivity of dopamine neurons to environmental neurotoxins and biogenic aldehydes; Aim 2 To determine the role of a-synuclein in the neuropathology and behavioral deficits in Aldh1a1/Aldh2 null mice; Aim 3 To determine the efficacy of accelerated aldehyde removal by aldehyde trapping agents on neuroprotection of midbrain dopamine neurons. The results of these studies may identify new therapeutic strategies for the treatment of Parkinson's disease.

描述（由申请人提供）： 帕金森氏病（PD）是仅次于阿尔茨海默氏病的年龄与年龄相关的神经退行性疾病，影响了65-85岁的人口中多达5％的PD临床表现，包括自愿运动，静止震颤，静止，肌肉剧烈的剧烈，肌肉僵硬和后态不稳定。主要的生化异常是在尼格拉（SN）和纹状体中多巴胺的严重丧失，这是由于Nigra中多巴胺能神经元及其在纹状体中的轴突末端的丧失所致。其他突出的病理特征包括存在由含有A-核蛋白和泛素的蛋白质聚集体组成的神经内夹杂物。尽管在过去二十年中的研究方面取得了长足的进步，但该疾病的病因和发病机理仍在很大程度上未知。尽管已经发现了引起PD样症状的单个基因突变，但它们占PD病例的数量相对较少。大多数PD病例被归类为特发性或未知原因。人类和动物研究已经建立了特发性或零星PD中环境暴露于Paraquat，Maneb和Rotenone之间的联系。尚未确定尚未完全了解具有不同作用机制的农药的机制可能导致PD，并且尚未确定预防或缓慢疾病进展的治疗策略。但是，我们实验室和其他人的越来越多的证据暗示醛排毒受损。我们的工作假设是，受损的醛排毒会导致“醛载荷”升高，包括增加水平和4-HNE水平。这些醛或其代谢产物可以用A-核蛋白形成加合物，从而导致有毒原纤维形成并最终导致细胞死亡。测试醛受损的假设 排毒与多巴胺能功能障碍有关；我们创建了两条小鼠，其中一条在两种醛脱氢酶同工酶，AldH1A1和AldH2中具有纯合突变，已知存在于中脑多巴胺神经元中，另一个存在于同一遗传背景上的鸡蛋中的野生型小鼠系中。然后，我们检查了ALDH1A1/ALDH2缺乏对其行为和神经化学表型的影响。我们的结果表明，缺乏ALDH1A1/ALDH2的小鼠在运动功能中表现出障碍，而L-DOPA逆转，多巴胺和代谢产物降低以及中脑多巴胺神经元的丧失。总体目的是从机械上测试醛负荷如何连接到多巴胺能功能障碍并评估醛作为治疗靶标。我们的具体目的是：目标1：确定醛解毒受损是否会增加多巴胺神经元对环境神经毒素和生物醛的敏感性；目标2确定A核蛋白在AldH1A1/AldH2 NULL小鼠中神经病理学和行为缺陷中的作用； AIM 3确定醛诱捕剂对中脑多巴胺神经元神经保护剂的加速醛去除的疗效。这些研究的结果可能会确定治疗帕金森氏病的新治疗策略。