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: 10259861
• 负责人: Pan Chen
• 金额: $ 21万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259861
• 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. !

项目总结： 锰是一种必需的金属，但过量接触会增加患帕金森氏症的风险 疾病(PD)。不宁腿综合症(RLS)是一种常见的神经系统疾病，在美国约10%的人中可见 人口。RLS的病理生物学与多巴胺能(DA能)功能和铁缺乏有关 缺乏症。有趣的是，在RLS中注意到PD患病率增加，反之亦然。BTBD9是 RLS的遗传危险因素。缺铁与大脑中锰的沉积增加有关，而锰的含量 大量的动态平衡和铁的运输途径，表明另一种金属的浓度，如 As，As。鉴于铁和锰之间已建立的联系 生物学方面，我们建议评估BTBD9是否可以调节锰诱导的细胞毒性和DAR 神经退行性变。此外，体内证据已将胰岛素/胰岛素样生长因子(IGF)信号联系起来 既有MN生物学，又有RLS。缺锰会导致葡萄糖不耐受和胰岛素生成减少， 而锰中毒则导致ATP和胰岛素/IGF受体表达下降。与此同时，糖尿病患者 与非糖尿病组相比，发生RLS的风险显著增加。这些观察结果支持链接 在(1)锰神经毒性、(2)DA神经生物学/帕金森病、(3)RLS和(4)IGF信号之间。然而，我们 胰岛素样生长因子信号网络中锰神经毒性的直接靶点缺乏机制基础及DA的作用 神经生物学在这些机制中发挥了作用。在这里，我们提出了一个直接调节IGF的蛋白质靶点(BTBD9) 保护信号免受锰暴露引起的氧化应激和线粒体功能障碍，从而 保护DAR的功能。我们将使用秀丽线虫(C.elegans)模型，因为它具有高度的 哺乳动物保守的神经遗传结构和IGF信号成分。我们的初步数据 为这一提议建立了必要的技术和概念基础。我们的假设将在 具体目的：1.探讨BTBD9/HPO-9的保护作用机制 锰对线虫的毒性及其在IGF信号转导中的作用我们将核实HPO-9是否会缓和 氧化应激、线粒体质量、膜电位、三磷酸腺苷的产生及其对IGF的调节 在暴露于锰时发出信号。特定目的2.确定HPO-9是否对锰诱导的DAR有调节作用 IGF信号对线虫的神经毒性作用。我们将评估DA能神经退行性变，DA依赖 锰暴露对蠕虫行为和DA浓度的影响。这项研究的结果将具有广泛的临床意义 和翻译的影响。我们的科学方法将揭示：(1)如果锰的全身性和/或神经元改变 可能与RLS中所见的DAR能功能受损有关(2)在MN之间建立功能联系 生物学、DAR功能和IGF信号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，这是多发性神经退行性变固有的过程 精神错乱。好了！