Neuronal Targets and Mechanisms of Manganese Neurotoxicity

锰神经毒性的神经靶点和机制

• 批准号: 10728773
• 负责人: Somshuvra Mukhopadhyay
• 金额: $ 61.41万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728773
• 关键词: Address; Adolescence; Adolescent; Adult; Air; Basal Ganglia; Behavioral; Behavioral Assay; Biological Assay; Biology; Cells; Child; Childhood; Corpus striatum structure; Development; Disease; Dopamine; Dopamine Agonists; Drug usage; Environmental Exposure; Exhibits; Exposure to; Functional disorder; Goals; Human; Infant; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Life; Manganese; Manganism; Metals; Microdialysis; Microscopy; Modeling; Motor Activity; Motor Skills; Movement; Mus; Nerve Degeneration; Neuronal Dysfunction; Neurons; Occupational; Oral; Parkinson Disease; Parkinsonian Disorders; Phenocopy; Phenotype; Population; Posture; Public Health; Role; Source; Substantia nigra structure; System; Testing; Therapeutic; Time; Work; dopaminergic neuron; drinking water; in vivo; infancy; innovation; motor deficit; motor disorder; motor impairment; mouse model; neurochemistry; neurotoxicity; neurotransmission; novel; pharmacologic; theories

ABSTRACT The essential metal manganese (Mn) accumulates in the basal ganglia at elevated levels and induces motor disease. Mn-induced motor disease is historically associated with occupational Mn exposure in adults. However, environmental exposure to elevated Mn has emerged as a more recent public health problem in infants, children and adolescents. Environmental Mn exposure in early-life substantially impairs motor function. But, the biology of Mn-induced motor disease in early-life is poorly understood, and there are no treatments for this condition. The fundamental question of how early-life, environmental Mn exposure impacts dopaminergic (DAergic) or GABAergic neurons in the basal ganglia that control movement to induce motor deficits is unanswered. This major knowledge gap exists because prior mechanistic work focused on the effects of Mn in adults. But, results from adults cannot be directly applied to early-life periods because environmental exposures are vastly different from occupational, early-life stages are more sensitive to Mn, and the impact of occupational Mn exposure on basal ganglia neurons is itself controversial. Our goal is to establish the effects of early-life, environmental Mn exposure on basal ganglia DAergic and GABAergic neurons that lead to motor disease. We will use innovative mouse models developed in the previous cycle that provide the feasibility, for the first time, to alter Mn levels specifically in DAergic or GABAergic neurons and isolate the role of the targeted neurons in Mn-induced motor disease. Our models are based on the neuron-specific knockout or knockin of the critical Mn efflux transporter SLC30A10. Pan-neuronal Slc30a10 knockouts had increased basal ganglia Mn levels and exhibited early-life motor deficits. Notably, Mn levels were elevated in targeted neurons of DAergic-specific or GABAergic-specific Slc30a10 knockouts, but only the DAergic-specific knockouts phenocopied the pan-neuronal strain and developed early-life motor deficits. These novel results lead to the hypothesis that Mn induces motor disease in early-life by targeting DAergic neurons. We will test our hypothesis through three specific aims. In Aim 1, we will use neuron-specific Slc30a10 knockout mice and test whether increasing Mn levels in DAergic, but not GABAergic, neurons enhances sensitivity to Mn-induced motor deficits. In Aim 2, we will use neuron-specific Slc30a10 knockin mice and test whether reducing Mn levels in DAergic, but not GABAergic, neurons protects against Mn neurotoxicity. We will use a combination of behavioral, microscopy, and neurochemical assays to distinguish between dysfunction or degeneration of DAergic or GABAergic neurons as the cause of early-life Mn-induced motor disease. In Aim 3, we will use a pharmacological approach and test whether dopamine agonists rescue early-life Mn-induced motor deficits. In totality, our studies (1) will establish a definitive neuronal mechanism of motor disease induced by environmental Mn exposure in early-life; and (2) may identify dopamine agonists to be a potential treatment for pediatric Mn-induced motor disease.

摘要 必需金属锰（Mn）在基底神经节中以升高的水平积累，并诱导运动 疾病锰引起的运动疾病在历史上与成人的职业性锰暴露有关。然而，在这方面， 环境暴露于高锰已成为最近的公共卫生问题，在婴儿，儿童， 和青少年。在生命早期的环境锰暴露大大损害运动功能。但是，生物学 锰诱导的运动疾病在生命早期的了解很少，也没有治疗这种情况。 早期生活的基本问题，环境锰暴露如何影响多巴胺能（DA能）或 基底神经节中的GABA能神经元控制运动以诱导运动缺陷，这一点尚未得到解答。这 主要的知识差距存在，因为以前的机械工作集中在成人锰的影响。但是，结果 不能直接应用于生命早期，因为环境暴露有很大的不同 职业性、早期生命阶段对锰更敏感，职业性锰暴露对 基底神经节神经元本身是有争议的。我们的目标是建立早期生活的影响，环境锰 暴露于基底神经节DA能和GABA能神经元，导致运动疾病。 我们将使用在前一个周期中开发的创新小鼠模型，这些模型提供了可行性， 时间，以改变DA能或GABA能神经元中的Mn水平，并分离靶向神经元的作用 锰引起的运动疾病我们的模型是基于神经元特异性敲除或敲入的关键 Mn外排转运蛋白SLC 30 A10。全神经元Slc 30 a10敲除增加了基底神经节Mn水平， 表现出早期运动缺陷值得注意的是，在DAergic特异性或 GABAergic特异性Slc 30 a10敲除，但只有DAergic特异性敲除表型模仿了泛神经元 并发展出早期的运动缺陷。这些新的结果导致锰诱导运动的假设， 通过靶向DA能神经元治疗早期疾病。我们将通过三个具体目标来检验我们的假设。 在目标1中，我们将使用神经元特异性Slc 30 a10敲除小鼠，并测试增加小鼠体内Mn水平是否会导致小鼠体内Mn水平升高。 DA能神经元而非GABA能神经元增强对Mn诱导的运动缺陷的敏感性。在目标2中，我们将使用 神经元特异性Slc 30 a10敲入小鼠，并测试是否降低DA能，但不降低GABA能， 神经元保护Mn神经毒性。我们将结合使用行为，显微镜， 神经化学测定以区分DA能或GABA能神经元的功能障碍或变性， 导致锰引起的早期运动疾病在目标3中，我们将使用药理学方法并测试 多巴胺激动剂是否能挽救锰诱导的早期运动缺陷。总的来说，我们的研究（1）将建立 在生命早期环境锰暴露诱导的运动疾病的确定性神经元机制;和（2） 可以确定多巴胺激动剂是一种潜在的治疗儿童锰诱导的运动疾病。

项目成果

Familial manganese-induced neurotoxicity due to mutations in SLC30A10 or SLC39A14.

• DOI: 10.1016/j.neuro.2017.07.030
• 发表时间: 2018-01
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Mukhopadhyay S

Generation and Validation of Tissue-Specific Knockout Strains for Toxicology Research.

用于毒理学研究的组织特异性敲除菌株的生成和验证。

• DOI: 10.1002/cptx.86
• 发表时间: 2019
• 期刊: Current protocols in toxicology
• 作者: Taylor,CherishA;Shawlot,William;Ren,JinXiang;Mukhopadhyay,Somshuvra
• 通讯作者: Mukhopadhyay,Somshuvra

Putative metal binding site in the transmembrane domain of the manganese transporter SLC30A10 is different from that of related zinc transporters.

• DOI: 10.1039/c8mt00115d
• 发表时间: 2018-08-15
• 期刊: Metallomics : integrated biometal science
• 作者: Zogzas CE;Mukhopadhyay S
• 通讯作者: Mukhopadhyay S

SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus.

• DOI: 10.1021/acschemneuro.8b00451
• 发表时间: 2019-01-16
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Carmona A;Zogzas CE;Roudeau S;Porcaro F;Garrevoet J;Spiers KM;Salomé M;Cloetens P;Mukhopadhyay S;Ortega R
• 通讯作者: Ortega R

Inherited Disorders of Manganese Metabolism.

• DOI: 10.1007/978-3-319-60189-2_3
• 发表时间: 2017-01-01
• 期刊: Advances in neurobiology
• 作者: Zogzas, Charles E;Mukhopadhyay, Somshuvra
• 通讯作者: Mukhopadhyay, Somshuvra