Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter

γ-突触核蛋白介导的去甲肾上腺素转运蛋白调节

• 批准号: 7730519
• 负责人: ANITA SIDHU
• 金额: $ 38.38万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730519
• 关键词: Actins; Adult; Affect; Aftercare; Age; Amoxapine; Animals; Antibodies; Antidepressive Agents; Applications Grants; Area; Attention; Autopsy; Behavior; Behavioral; Binding; Binding Proteins; Brain; Breast Cancer Cell; Breast Carcinoma; Buffers; Cell Nucleus; Cell surface; Cells; Characteristics; Chronic; Co-Immunoprecipitations; Complementary DNA; Complex; Computer software; Cytoplasm; Cytoskeletal Proteins; Cytoskeleton; Dactinomycin; Data; Desipramine; Development; Dose; Down-Regulation; Drug Addiction; Drug Delivery Systems; Drug abuse; Equilibrium; Functional disorder; Gamma synuclein; Genetic Transcription; Grant; Guanosine Triphosphate; Homeostasis; Human; Imipramine; Immunoprecipitation; In Vitro; Inbred WKY Rats; Incidence; Individual; Inferior frontal gyrus; Knockout Mice; Label; Laboratories; Lead; Link; Maintenance; Malignant Epithelial Cell; Measures; Mediating; Membrane; Messenger RNA; Methionine; Microtubules; Modeling; Molecular; Mood Disorders; Moods; Mus; Neurodegenerative Disorders; Neurons; Nocodazole; Norepinephrine; Nuclear; Nucleotides; Nylons; Occupations; Parkinson Disease; Patients; Pharmaceutical Preparations; Physiologic pulse; Protein Family; Proteins; Publishing; RNA; Rattus; Reaction; Reagent; Regulation; Relative (related person); Reporting; Research; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Role; Run-On Assays; Series; Signal Transduction; Sleep; Synaptic plasticity; Synaptosomes; Synuclein Family; System; Time; Tissues; Transgenic Mice; Transgenic Organisms; Tubulin; Vision Disorders; Western Blotting; Wistar Rats; alpha synuclein; clinically relevant; depression; depressive symptoms; frontal lobe; hormone regulation; in vitro Model; in vivo; in vivo Model; insight; mRNA Stability; member; neurochemistry; neurogenesis; neurotransmission; noradrenaline transporter; noradrenergic; novel; overexpression; presynaptic; promoter; protein expression; reboxetine; response; restoration; synuclein; synucleinopathy; tau Proteins; trafficking; trizol; vigilance

Aberrant norepinephrine [NE] neurotransmission in the human brain is linked to mood disorders, depression, drug addiction and neurodegenerative diseases. 􀈖-synuclein [􀈖-Syn], a member of the synuclein family of proteins, is expressed in monoaminergic neurons, but its function in the brain is not known. We have shown that 􀄮-Syn can modulate the function and trafficking of the NE transporter [NET], through interactions with the microtubule [MT] cytoskeleton. We show here that 􀈖-Syn can also regulate these NET activities. Such modulation by 􀈖-Syn is unique to NET. In a rat model of depression, there is overexpression of 􀈖-Syn, causing NET function and trafficking to be dysregulated and unresponsive to the effects of nocodazole [a MT destabilizing agent], probably due to tight binding of the 􀈖-Syn/NET complex to the MT cytoskeleton. Chronic treatment of these animals with desipramine [a NET blocker] reduces 􀈖-Syn protein expression, while increasing 􀄮-Syn levels, permitting NET to be appropriately regulated by 􀄮-Syn, with full restoration of nocodazole sensitivity. In postmortem brains from patients with depression, we also show that 􀈖-Syn is overexpressed, adding clinical relevance for a role for 􀈖-Syn in the genesis and maintenance of depression in humans. We hypothesize that 􀈖-Syn acts as a prodepressant, and that imbalances in 􀈖-Syn/􀄮-Syn expression levels is central to the genesis of depression. When overexpressed, 􀈖-Syn overrides the normative regulation of NET by 􀄮-Syn. Therefore, targeting 􀈖-Syn expression levels may be key to controlling depression in humans. We will investigate here in detail the cellular and molecular mechanisms by which desipramine reduces 􀈖-Syn levels in both in vitro and in vivo models, which express either 􀈖-Syn alone or both 􀈖-Syn and NET, in the presence or absence of 􀄮-Syn. We will also analyze the mechanisms by which other NET antidepressants decrease 􀈖-Syn expression in in vitro models. Finally, we will measure neurochemical and behavioral responses to NET antidepressants in 􀄮-Syn overexpressing transgenic mice, as well as in 􀄮-Syn knock-out mice. From these studies we will be able to assess the mechanisms by which 􀈖-Syn expression is regulated as well as ascertain the physiopathological relevance of such regulation in the genesis of depression.

人脑中的异常去甲肾上腺素[NE]神经传递与情绪障碍，抑郁症，药物成瘾和神经退行性疾病有关。 synuclein蛋白质家族的成员 - synuclein [-syn]在单胺能神经元中表达，但其在大脑中的功能尚不清楚。我们已经表明，◎-syn可以通过与微管[mt]细胞骨架的相互作用来调节NE转运蛋白[NET]的功能和运输。我们在这里表明 - syn也可以调节这些净活动。 ◎-Syn的调制是网络独有的。在大鼠抑郁模型中，◎-syn的过度表达，导致净功能和运输对诺科唑[MT不稳定剂]的影响不反应，这可能是由于对Mt Cytoskeleton的◎-Syn/Net复合物的紧密结合。用去丙胺[净阻滞剂]对这些动物进行慢性治疗可降低-syn蛋白的表达，同时增加◎-syn水平，允许NET受到◎-Syn的适当调节，并完全恢复了诺科唑敏感性。在抑郁症患者的后大脑中，我们还表明◎-syn过表达，为◎-syn在人类抑郁症的起源和维持中的作用增加了临床意义。 我们假设◎-syn充当产生的抑制剂，并且◎-syn/◎-syn表达水平的失衡对于抑郁的起源是核心。当过表达时，◎-syn覆盖了net的正常调节，由◎-syn覆盖。 因此，靶向-SYN表达水平可能是控制人类抑郁症的关键。我们将在这里详细研究desipramine在体外和体内模型中降低desipramine在存在或不存在◎-syn的情况下单独表达◎-syn和net的细胞和分子机制。我们还将分析其他净抗抑郁药在体外模型中降低-SYN表达的机制。最后，我们将测量过表达的转基因小鼠以及◎-syn敲除小鼠中对◎-syn过表达的抗抑郁药的神经化学和行为反应。从这些研究中，我们将能够评估调节◎-syn表达的机制，并确定这种调节在抑郁起源中的生理病理学相关性。