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: 8971961
• 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/8971961
• 关键词: 1-Methyl-4-phenylpyridinium; Accounting; Affect; Age; Aldehydes; Alzheimer' s Disease; Animals; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Cell Death; Clinical; Corpus striatum structure; 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; Health; 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; diagnostic biomarker; dopaminergic neuron; environmental agent; neurochemistry; neuropathology; neuroprotection; neurotoxic; novel therapeutic intervention; overexpression; preclinical study; prevent; protein aggregate; protein folding; 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大年龄相关性神经退行性疾病，影响高达5%的65 - 85岁的人群，PD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（SN）和纹状体中多巴胺的严重损失，这是由于黑质中多巴胺能神经元及其纹状体中轴突终末的损失造成的。其他突出的病理学特征包括存在由含有α-突触核蛋白和泛素的蛋白质聚集体组成的神经元内包涵体。尽管在过去的二十年里研究取得了很大的进步，但该病的病因和发病机制在很大程度上仍然未知。虽然已确定家庭与单基因突变，导致PD样症状，他们占相对较少的PD病例。大多数PD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，代森锰和鱼藤酮在特发性或散发性PD之间的联系。暴露于具有不同作用机制的农药可能导致PD的机制尚未完全了解，预防或减缓疾病进展的治疗策略尚未确定。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受损。我们的工作假设是醛解毒受损导致“醛负荷”升高，包括DOPAL和4-HNE水平升高。这些醛或其代谢物可与α-突触核蛋白形成加合物，导致形成毒性原纤维并最终导致细胞死亡。为了验证乙醛受损的假设 解毒机制与多巴胺能功能障碍有关; 2我们建立了两个品系的小鼠，一个在已知存在于中脑多巴胺神经元中的两种醛脱氢酶同工酶Aldh 1a 1和Aldh 2中具有纯合突变，另一个品系的野生型小鼠来自相同遗传背景的同窝小鼠。然后，我们研究了Aldh 1a 1/Aldh 2缺乏对他们的行为和神经化学表型的影响。我们的研究结果表明，缺乏Aldh 1a 1/Aldh 2的小鼠表现出运动功能障碍，L-DOPA，多巴胺和代谢物减少，中脑多巴胺神经元丢失。总体目标是测试机械地确定醛负荷增加如何与多巴胺能功能障碍相关，并评估醛作为治疗靶点。我们的具体目标是：目标1：目的2确定乙醛解毒受损是否增加多巴胺神经元对环境神经毒素和生物源性醛的敏感性;目的3确定醛捕获剂加速乙醛清除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发现新的治疗策略，用于治疗帕金森病。