BTBD9, a novel regulator of manganese-induced neurotoxicity

BTBD9，锰引起的神经毒性的新型调节剂

• 批准号: 10055864
• 负责人: Pan Chen
• 金额: $ 25.18万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055864
• 关键词: Alleles; Alzheimer' s Disease; Animals; Architecture; Attenuated; Behavior; Behavioral; Biochemical; Biology; Brain; Caenorhabditis elegans; Cell Death; Clinical; Clinical Research; Data; Dependence; Deposition; Diabetes Mellitus; Dopamine Agonists; Etiology; Exposure to; Glucose Intolerance; Goals; Health Hazards; Homeostasis; Huntington Disease; Impairment; Insulin; Insulin-Like Growth Factor Receptor; Iron; Isoprostanes; Larva; Leg; Light; Link; Manganese; Mediating; Membrane Potentials; Metabolic; Metals; Mitochondria; Modeling; Morphology; Movement; Nematoda; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Occupational Health; Outcome; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Patients; Permeability; Play; Population; Prevalence; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Research; Restless Legs Syndrome; Risk; Role; Signal Pathway; Signal Transduction; Somatomedins; Stress; Technology; Testing; Therapeutic Intervention; Toxic effect; cytotoxicity; genetic risk factor; in vivo; insight; iron deficiency; iron supplementation; manganese chloride; manganese deficiency; mitochondrial dysfunction; mutant; nervous system disorder; neurogenetics; neurotoxic; neurotoxicity; non-diabetic; novel; novel therapeutics; overexpression; prevent; protein aggregation; receptor expression; response; therapeutic protein; transcription factor; translational impact

Project Summary: Manganese (Mn) is an essential metal, but excess exposure is associated with increased risk for Parkinson's disease (PD). Restless legs syndrome (RLS) is a common neurological disorder seen in ~10% of the US population. The pathobiology of RLS has been linked to deficits in dopaminergic (DAergic) function and Fe deficiency. Interestingly, increased prevalence of PD is noted in RLS, and vice versa. BTBD9 is one of the genetic risk factors for RLS. Fe-deficiency is associated with increased brain deposition of Mn, and Mn shares numerous homeostatic and transport pathways with Fe, suggesting that concentrations of another metal, such as Mn, may opportunistically increase upon Fe deficiency. Given the established link between Fe and Mn biology, we propose to evaluate whether BTBD9 may regulate Mn-induced cytotoxicity and DAergic neurodegeneration. Furthermore, in vivo evidence has linked insulin/insulin-like growth factor (IGF) signaling with both Mn biology and RLS. Mn-deficiency caused glucose intolerance and reduced insulin production, while Mn toxicity caused reduced ATP and insulin/IGF receptor expression. Meanwhile, patients with diabetes have significantly increased risk to develop RLS than non-diabetic groups. These observations support links between (1) Mn neurotoxicity, (2) DA neurobiology/ parkinsonism, (3) RLS, and (4) IGF signaling. However, we lack a mechanistic basis for the direct targets of Mn neurotoxicity in IGF signaling networks and the role DA neurobiology plays in these mechanisms. Here, we propose a direct protein target (BTBD9) regulating IGF signaling to protect against oxidative stress and mitochondrial dysfunction induced by Mn exposure, thus protecting DAergic function. We will use the Caenorhabditis elegans (C. elegans) model as it shares a highly conserved neurogenetic architecture and IGF signaling components with mammalians. Our preliminary data established the requisite technology and conceptual basis for this proposal. Our hypothesis will be tested in the following Specific Aims:!Specific Aim 1. Investigate the protective mechanism of BTBD9/HPO-9 against Mn-induced toxicity and its role in IGF signaling in C. elegans. We will verify whether HPO-9 moderates oxidative stress, mitochondrial mass, membrane potential, ATP production and how it regulates the IGF signaling upon Mn exposure. Specific Aim 2. Determine if HPO-9 modulates Mn-induced DAergic neurotoxicity via IGF signaling in C. elegans. We will assess DAergic neurodegeneration, DA-dependent behavior and DA concentrations in worms upon Mn exposure. Results from this study will have a broad clinical and translational impact. Our scientific approach will (1) reveal if systemic and/or neuronal alterations in Mn may contribute to the impaired DAergic function seen in RLS (2) establish a functional link between Mn biology, DAergic functionality and IGF signaling 3) provide a new target protein for therapeutic interventions to ameliorate oxidative stress and mitochondrial dysfunction, a process inherent to multiple neurodegenerative disorders. !

项目概要： 锰（Mn）是一种必需金属，但过量暴露与帕金森病风险增加有关 疾病（PD）。不宁腿综合征（RLS）是一种常见的神经系统疾病，约10%的美国人患有这种疾病。 人口RLS的病理生物学与多巴胺能（DA能）功能和铁的缺乏有关。 缺陷有趣的是，在RLS中注意到PD的患病率增加，反之亦然。BTBD 9是一个 RLS的遗传风险因素。铁缺乏与锰的脑沉积增加有关，并且锰份额 许多稳态和运输途径与铁，这表明浓度的另一种金属，如 如锰，可能会机会性地增加时，铁缺乏。考虑到铁和锰之间的联系 生物学，我们建议评估BTBD 9是否可以调节Mn诱导的细胞毒性和DA能 神经变性此外，体内证据表明胰岛素/胰岛素样生长因子（IGF）信号转导 与锰生物学和RLS。锰缺乏导致葡萄糖耐受不良和胰岛素分泌减少， 而Mn毒性导致ATP和胰岛素/IGF受体表达降低。同时，糖尿病患者 发生RLS的风险比非糖尿病组显著增加。这些观察支持链接 （1）Mn神经毒性，（2）DA神经生物学/帕金森综合征，（3）RLS和（4）IGF信号传导之间的关系。但我们 缺乏锰神经毒性在IGF信号传导网络中的直接靶点的机制基础， 神经生物学在这些机制中发挥作用。在这里，我们提出了一个直接的蛋白质靶点（BTBD 9）调节IGF 信号传导以保护免受由Mn暴露诱导的氧化应激和线粒体功能障碍，因此 保护DA能功能。我们将使用秀丽隐杆线虫（C. elegans）模型，因为它共享一个高度 保守的神经遗传结构和IGF信号成分。我们的初步数据 为这一提议奠定了必要的技术和概念基础。我们的假设将在 具体目标：！具体目标1.探讨BTBD 9/HPO-9对人肝癌细胞的保护机制。 锰对C.优美的我们将验证HPO-9是否 氧化应激，线粒体质量，膜电位，ATP产生以及它如何调节IGF 在Mn暴露时发出信号。具体目标2。确定HPO-9是否调节Mn诱导的DA能 C.通过IGF信号传导的神经毒性优美的我们将评估DA能神经变性、DA依赖性 行为和DA浓度在蠕虫锰暴露。这项研究的结果将具有广泛的临床意义。 和翻译影响。我们的科学方法将（1）揭示Mn的全身和/或神经元改变 可能导致RLS中观察到的DA能功能受损（2）在Mn 生物学、DA能功能和IGF信号传导3）为治疗干预提供了新的靶蛋白， 改善氧化应激和线粒体功能障碍，这是多种神经退行性疾病固有的过程。 紊乱!