Detoxification of Biogenic Aldehydes in Parkinson's Disease

生物醛在帕金森病中的解毒作用

• 批准号: 10291812
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291812
• 关键词: 4 hydroxynonenal; Affect; Age-Months; Aldehydes; Alzheimer' s Disease; Animals; Behavioral; Biochemical; Biological Assay; Brain; California; Clinical; Corpus striatum structure; Disease; Disease Progression; Dopamine; Drug Metabolic Detoxication; Environmental Exposure; Etiology; Exhibits; Exposure to; FDA approved; Family; Farming Community; Female; Functional disorder; Funding; Gait; Gene Mutation; Genes; Genetic Polymorphism; Human; Hydralazine; Impairment; Isoenzymes; Knockout Mice; Link; Lipid Peroxidation; Maneb; Measures; Metabolism; Midbrain structure; Military Personnel; Mitochondria; Modeling; Motor; Movement; Mus; Muscle Rigidity; Mutation; Nerve Degeneration; Paraquat; Parkinson Disease; Pathogenesis; Pathologic; Patients; Performance; Peripheral; Persons; Pesticides; Pharmaceutical Preparations; Population; Presynaptic Terminals; Reducing Agents; Research; Rest Tremor; Risk; Role; Rotenone; Safety; Substantia nigra structure; Symptoms; Testing; Tissues; Toxic Environmental Substances; Transgenic Mice; Transgenic Organisms; Tyrosine 3-Monooxygenase; Ubiquitin; United States; Veterans; Work; adduct; age related; age related neurodegeneration; aged; agricultural pesticide; aldehyde dehydrogenases; alpha synuclein; behavior measurement; behavior test; behavioral study; diagnostic biomarker; dopaminergic neuron; environmental agent; epidemiology study; human old age (65+); in vivo; in vivo evaluation; male; military veteran; neurochemistry; neuroinflammation; new therapeutic target; overexpression; posture instability; preclinical study; prevent; protein aggregation; targeted agent; targeted treatment; therapeutic target; treatment strategy

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. Veterans are at increased risk for PD because the veteran population is older than the United States population as a whole and because veterans are more likely to have been exposed to toxic environmental agents during deployment. 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, the majority of PD cases are classified as idiopathic. Animal studies, and subsequent epidemiological studies, have established a link between environmental exposure to agents such as paraquat, maneb and rotenone in idiopathic or sporadic PD. The mechanisms by which exposure to pesticides with different mechanisms of action may increase the risk of 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. For example, cytosolic aldehyde dehydrogenase (ALDH1) expression is reduced in the SN of PD patients. The widespread reduction in ALDH1 in central and peripheral tissues in sporadic PD has suggested the possibility of using it as a diagnostic biomarker. Epidemiological studies of the farming communities in the Central Valley in California have linked polymorphisms in mitochondrial aldehyde dehydrogenase (ALDH2) to enhanced risk of PD in people exposed to agricultural pesticides. Our working hypothesis is that impaired aldehyde detoxification consequent to exposure to environmental agents, and/or reduced aldehyde dehydrogenase expression leads to elevated “aldehyde load” including increased levels of 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 4-hydroxynonenal (4-HNE), aldehyde products of dopamine metabolism and lipid peroxidation, respectively. We hypothesize that these aldehydes may form adducts with α-synuclein producing toxic fibrils that cause neurodegeneration. To test this hypothesis in vivo, we created a line of mice with homozygous mutations in the only two aldehyde dehydrogenase isozymes, Aldh1a1 and Aldh2, known to be present in midbrain dopamine neurons. The Aldh1a1-/-xAldh2-/- (DKO) mice exhibit elevation of DOPAL and 4-HNE that precedes age-related impairments in motor function, reduced dopamine and metabolites, and loss of midbrain dopamine neurons starting around 12 months of age and continuing to progress to at least 23 months of age. We then crossed this line of mice to mice overexpressing human wild-type α-synuclein to create a triple transgenic line (TTG) to determine the downstream effects of elevated biogenic aldehydes on α-synuclein. Preliminary behavioral studies show that elevated biogenic aldehydes accelerate the age-related decline in measures of gait, rotarod performance, pole-test and fine motor performance in TTG mice. Our overall aim in the next period of funding is to understand mechanistically the link between biogenic aldehydes and α-synuclein in vivo in dopaminergic dysfunction. We will then evaluate aldehydes as therapeutic targets for FDA approved agents that reduce toxic aldehyde levels to slow or prevent the neuropathological and behavioral manifestations of PD. The Specific Aims are: Specific Aim 1: To determine whether elevated biogenic aldehydes exacerbates behavioral deficits in mice overexpressing human wildtype αSyn. Specific Aim 2: To determine whether elevated biogenic aldehydes exacerbate neurochemical and histopathological changes in mice overexpressing human wildtype αSyn. Specific Aim 3: To determine whether hydralazine, an agent that traps aldehydes, will rescue behavioral and neurochemical changes observed in Aims 1 and 2. The work proposed will potentially identify new therapeutic targets and agents for treatment of veterans with Parkinson's disease.

帕金森病（PD）是第二大最常见的年龄相关性神经退行性疾病，仅次于 阿尔茨海默病，影响65 - 85岁人口的5%。退伍军人面临的风险增加 PD是因为退伍军人人口比美国人口整体年龄大， 更有可能在部署期间暴露于有毒环境因子。尽管在这方面取得了巨大进步， 经过近二十年的研究，该病的病因和发病机制仍不清楚。 虽然已确定具有单基因突变的家族，但大多数PD病例被归类为 特发性的动物研究和随后的流行病学研究已经建立了 环境暴露于百草枯、代森锰和鱼藤酮等药物治疗特发性或散发性PD。的 暴露于具有不同作用机制的农药可能增加PD风险的机制 尚未完全了解，预防或减缓疾病进展的治疗策略尚未得到 鉴定然而，来自我们实验室和其他实验室的越来越多的证据表明， 解毒例如，细胞溶质醛脱氢酶（ALDH 1）表达在PD的SN中减少， 患者散发性PD患者的中枢和外周组织中ALDH 1的广泛减少表明 将其用作诊断生物标志物的可能性。2004年农业社区流行病学研究 加州的中央谷已经将线粒体醛脱氢酶（ALDH 2）的多态性与 暴露于农药的人患PD的风险增加。 我们的工作假设是，醛解毒受损的结果暴露于 环境因素和/或醛脱氢酶表达降低导致“醛脱氢酶”表达升高。 包括增加的3，4-二羟基苯乙醛（DOPAL）和4-羟基壬烯醛 （4-HNE）、多巴胺代谢的醛类产物和脂质过氧化。我们 假设这些醛可能与α-突触核蛋白形成加合物，产生毒性纤维， 神经变性为了在体内验证这一假设，我们建立了一个小鼠系， 已知存在于中脑多巴胺中仅有两种醛脱氢酶同工酶Aldh 1a 1和Aldh 2 神经元Aldh 1a 1-/-xAldh 2-/-（DKO）小鼠表现出DOPAL和4-HNE的升高，其先于年龄相关的 运动功能受损，多巴胺和代谢物减少，中脑多巴胺神经元丢失 从大约12个月大开始，并继续发展到至少23个月大。然后我们穿过这个 小鼠系与过表达人野生型α-突触核蛋白的小鼠，以创建三重转基因系（TTG）， 确定升高的生物醛对α-突触核蛋白的下游影响。初步行为研究 表明升高的生物醛加速了与年龄相关的步态、转棒、 在TTG小鼠中的性能、极测试和精细运动性能。我们在下一个供资期的总体目标 是从机理上理解生物醛和α-突触核蛋白在体内的联系， 多巴胺能功能障碍然后，我们将评估醛作为FDA批准的治疗靶点， 降低毒性醛水平以减缓或预防神经病理学和行为学损害的药剂 PD的表现。具体目的是：具体目的1：确定是否升高的生物源性 醛类可加重过表达人野生型αSyn小鼠的行为缺陷。具体目标2： 确定升高的生物醛是否会加剧神经化学和组织病理学变化， 过表达人野生型αSyn的小鼠具体目标3：确定肼苯哒嗪，一种 捕获醛类，将挽救在目标1和2中观察到的行为和神经化学变化。工作 提出的将有可能确定新的治疗靶点和药物，用于治疗退伍军人， 帕金森氏症。