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)： 帕金森病(Parkinson‘s Disease，PD)是仅次于阿尔茨海默病的第二种最常见的神经退行性疾病，影响65-85岁人群的5%。帕金森病的临床表现包括自主运动缓慢、静止性震颤、肌肉僵硬和姿势不稳定。主要的生化异常是黑质和纹状体中的多巴胺的严重丢失，这是由于黑质中的多巴胺能神经元及其纹状体中的轴突终末的丢失所致。其他显著的病理特征包括神经元内包涵体的存在，这些包涵体由含有α-突触核蛋白和泛素的蛋白质聚集体组成。尽管在过去20年的研究中取得了长足的进步，但这种疾病的病因和发病机制在很大程度上仍不清楚。虽然已经发现有导致帕金森病症状的单基因突变，但它们在帕金森病病例中所占的比例相对较小。大多数帕金森病病例被归类为特发性或原因不明。人类和动物研究已经确定了环境暴露于百草枯、甘露醇和鱼藤酮与特发性或散发性帕金森病之间的联系。接触不同作用机制的杀虫剂可能导致帕金森病的机制尚不完全清楚，预防或减缓疾病进展的治疗策略也尚未确定。然而，来自我们实验室和其他实验室的越来越多的证据表明，乙醛解毒作用受损。我们的工作假设是，受损的醛排毒会导致“醛负荷”增加，包括DOPAL和4-HNE水平的增加。这些醛或其代谢产物可以与α-突触核蛋白形成加合物，导致有毒纤维的形成，最终导致细胞死亡。来检验损害乙醛的假设 从机制上讲，解毒与多巴胺能功能障碍有关；我们创造了两个小鼠品系，一个在两个乙醛脱氢酶同工酶Aldh1a1和ALDH2中存在纯合子突变，已知存在于中脑多巴胺神经元中，另一个品系为野生型小鼠，来自相同遗传背景的后代。然后，我们研究了Aldh1a1/ALDH2缺乏对它们的行为和神经化学表型的影响。我们的结果表明，Aldh1a1/ALDH2基因缺陷的小鼠表现出运动功能的损害，这种损害被L-多巴逆转，多巴胺和代谢物减少，以及中脑多巴胺神经元的丢失。总体目标是进行机械测试，确定醛负荷增加与多巴胺能功能障碍之间的联系，并评估醛作为治疗靶点。我们的具体目标是：目的1：确定醛脱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；目的2确定α-突触核蛋白在Aldh1a1/ALDH2基因缺失小鼠神经病理和行为缺陷中的作用；目的3确定醛捕捉剂加速除醛对中脑多巴胺神经元的神经保护作用。这些研究的结果可能会确定治疗帕金森氏症的新治疗策略。