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: 10516030
• 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/10516030
• 关键词: 4 hydroxynonenal; Acceleration; Affect; Age Months; Aldehydes; Alzheimer' s Disease; Animals; Behavioral; Biochemical; Biological Assay; Brain; California; Classification; 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; Therapeutic Agents; 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; male; military veteran; neurochemistry; neuroinflammation; neuropathology; neuroprotection; new therapeutic target; overexpression; posture instability; preclinical study; prevent; protein aggregation; sporadic Parkinson' s Disease; 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) 是第二常见的与年龄相关的神经退行性疾病，仅次于 阿尔茨海默氏病影响 65 至 85 岁人群中高达 5% 的人。退伍军人面临更大的风险 PD 因为退伍军人人口比美国整体人口年龄大，而且因为退伍军人 在部署过程中更有可能接触有毒环境介质。尽管取得了巨大进步 经过过去二十年的研究，该病的病因和发病机制仍然很大程度上未知。 尽管已发现家族存在单基因突变，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两者之间的联系 特发性或散发性帕金森症中环境暴露于百草枯、代森锰和鱼藤酮等药剂。这 接触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，并且尚未制定预防或减缓疾病进展的治疗策略 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醛受损 排毒。例如，PD 的 SN 中胞浆醛脱氢酶 (ALDH1) 表达减少 患者。散发性 PD 中枢和外周组织中 ALDH1 的广泛减少表明 将其用作诊断生物标志物的可能性。农村地区农业社区流行病学研究 加利福尼亚州中央山谷将线粒体乙醛脱氢酶 (ALDH2) 的多态性与 接触农业农药的人患帕金森病的风险增加。 我们的工作假设是，接触乙醛会导致乙醛解毒受损 环境因素和/或醛脱氢酶表达减少导致“醛 负荷”，包括 3,4-二羟基苯乙醛 (DOPAL) 和 4-羟基壬烯醛水平增加 (4-HNE)，分别是多巴胺代谢和脂质过氧化的醛产物。我们 假设这些醛可能与 α-突触核蛋白形成加合物，产生有毒原纤维，导致 神经变性。为了在体内验证这一假设，我们创建了一系列具有纯合突变的小鼠 已知存在于中脑多巴胺中的唯一两种乙醛脱氢酶同工酶 Aldh1a1 和 Aldh2 神经元。 Aldh1a1-/-xAldh2-/- (DKO) 小鼠表现出 DOPAL 和 4-HNE 的升高，先于年龄相关的升高 运动功能受损、多巴胺和代谢物减少以及中脑多巴胺神经元丧失 从 12 个月左右开始，持续发展到至少 23 个月大。然后我们就跨越了这个 将小鼠品系与过表达人类野生型 α-突触核蛋白的小鼠进行培育，创建三重转基因品系 (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 表明生物醛的升高会加速与年龄相关的步态、旋转测量指标的下降 TTG 小鼠的性能、杆测试和精细运动性能。我们下一期融资的总体目标 是从机制上理解体内生物醛和 α-突触核蛋白之间的联系 多巴胺能功能障碍。然后我们将评估醛作为 FDA 批准的治疗靶点 降低有毒醛水平以减缓或预防神经病理和行为的药物 PD 的表现。具体目标是： 具体目标 1：确定生物源性是否升高 醛会加剧过度表达人类野生型 αSyn 的小鼠的行为缺陷。具体目标 2： 确定生物醛含量升高是否会加剧神经化学和组织病理学变化 过度表达人类野生型 αSyn 的小鼠。具体目标 3：确定肼屈嗪（一种药物）是否 捕获醛，将挽救目标 1 和 2 中观察到的行为和神经化学变化。 提议将有可能确定新的治疗靶点和药物来治疗退伍军人 帕金森病。