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: 10043827
• 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/10043827
• 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; 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.

帕金森氏病（PD）是第二大流行的与年龄有关的神经退行性疾病，仅次于 阿尔茨海默氏病，影响65至85岁的人口中多达5％。退伍军人的风险增加 PD是因为退伍军人人口比整个美国的人口年龄大，而且退伍军人 部署期间，更有可能接触到有毒的环境代理商。尽管大步很大 在过去的二十年中，该疾病的病因和发病机理在很大程度上尚不清楚。 尽管已经确定了单个基因突变的家庭，但大多数PD病例被归类为 特发性。动物研究以及随后的流行病学研究已经建立了 特发性或零星PD中的环境暴露于Paraquat，Maneb和Rotenone等药物。这 暴露于不同作用机制的农药的机制可能会增加PD的风险 尚未完全了解，预防或缓慢疾病进展的治疗策略尚未 确定。但是，我们实验室和其他人的越来越多的证据暗示了醛受损 解毒。例如，胞质醛脱氢酶（ALDH1）表达在PD的SN中降低 患者。散发性PD的中央和周围组织中ALDH1的宽度减小已表明 将其用作诊断生物标志物的可能性。农业社区的流行病学研究 加利福尼亚的中央山谷已将线粒体醛脱氢酶（ALDH2）中的多态性联系在一起 暴露于农业农药的人的PD风险增加。 我们的工作假设是，导致暴露的醛排毒受损 环境剂和/或降低醛脱氢酶表达导致醛升高 负载”，包括增加3,4-二羟基苯基甲醛（dopal）和4-羟基烯烯酸的水平 （4-HNE），分别是多巴胺代谢和脂质过氧化的醛产物。 假设这些醛可能与α-突触核蛋白产生有毒原纤维形成加合物 神经变性。为了在体内检验这一假设，我们创建了一系列具有纯合突变的小鼠 仅有两个醛脱氢酶同工酶Aldh1a1和Aldh2，已知存在于中脑多巴胺中 神经元。 aldh1a1 - / - xaldh2 - / - （dko）小鼠在与年龄有关 运动功能障碍，减少多巴胺和代谢产物以及中脑多巴胺神经元的丧失 从大约12个月大的时候开始，并继续发展至至少23个月大。然后我们越过这个 对过表达人类野生型α-突触核蛋白的小鼠的小鼠线，形成三重转基因线（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 表明升高的生物基因醛加速了步态测量的年龄相关下降 TTG小鼠的性能，杆测试和精细运动性能。我们在下一阶段的总体目标 是在机械上理解生物醛与体内α-核蛋白之间的联系 多巴胺能功能障碍。然后，我们将评估醛作为FDA批准的治疗靶标 降低有毒醛水平的药物会减慢或预防神经病理和行为 PD的表现。具体目的是：特定目的1：确定升高生物源 醛加剧了过表达人类野生型αSyn的小鼠的行为。具体目标2： 确定升高的生物醛是否加剧了神经化学和组织病理学的变化 过表达人类野生型αSyn的小鼠。特定目的3：确定氢嗪是否是一种代理 捕获醛，将在目标1和2中观察到的行为和神经化学变化。 拟议的将有可能确定新的治疗靶标和药物，以治疗退伍军人 帕金森氏病。