Role of TPH2 and 5HT Neuronal Loss in Non-motor Symptoms of Parkinson's

TPH2 和 5HT 神经元丢失在帕金森病非运动症状中的作用

• 批准号: 8277532
• 负责人: Donald M Kuhn
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277532
• 关键词: Accounting; Achievement; Anxiety; Anxiety Disorders; Aromatic-L-Amino-Acid Decarboxylases; Biological; Bradykinesia; Brain; Cause of Death; Cells; Cessation of life; Cysteine; Degenerative Disorder; Dementia; Deposition; Disease; Dopamine; Enzymes; Equilibrium; General Population; Goals; Gold; Individual; Life Expectancy; Light; Link; Mediator of activation protein; Mental Depression; Midbrain structure; Modeling; Modification; Molecular; Morbidity - disease rate; Motor; Movement Disorders; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidants; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathologic Processes; Pathology; Patients; Pharmacotherapy; Positioning Attribute; Prevalence; Process; Protein Biosynthesis; Protein Conformation; Proteins; Quality of life; Research; Role; Rotenone; Serotonin; Sleep Disorders; Symptoms; System; Time; Tremor; Tryptophan 5-monooxygenase; Veterans; Wild Type Mouse; abstracting; computerized data processing; cysteine rich protein; cytotoxicity; disability; dopaminergic neuron; equilibration disorder; in vivo; loss of function; mortality; neurobiological mechanism; neurochemistry; neuron loss; neuropsychiatry; neurotoxic; nigrostriatal pathway; oxidation; protein aggregation; protein degradation; protein misfolding; response; sensor

DESCRIPTION (provided by applicant): Project summary/abstract Parkinson's disease (PD) is the prototypic degenerative disease of the dopamine (DA) neuronal system. The progressive loss of nigrostriatal DA neurons gradually leads to a severe movement disorder characterized by tremor, rigidity, bradykinesia and impaired balance. PD accounts for significant morbidity and mortality among veterans and the general population. It is not widely appreciated but the serotonin (5HT) neuronal system is also severely impacted in PD. Brains from individuals with PD have significantly lower levels of 5HT, reduced 5HT synthesis and turnover, reductions in the amount of tryptophan hydroxylase (TPH2) and losses in the number of intact 5HT neurons. Decrements in 5HT neurochemical function are highly significant in light of the fact that approximately 80% of PD patients suffer from co-morbid neuropsychiatric conditions like depression, sleep disorders, anxiety and dementia. Many of these conditions have been linked to dysfunctional 5HT neurochemistry. L-DOPA is the gold-standard pharmacotherapy for PD. L-DOPA enters the brain and is converted to DA by the ubiquitous L-aromatic amino acid decarboxylase (L-AADC). This treatment increases DA in all cells expressing L-AADC to include DA neurons, as desired, as well as in 5HT and other neurons. This inappropriate deposition of DA within 5HT neurons can alter their neurochemical function and subject them to heightened oxidative stress from non- enzymatic breakdown products of L-DOPA and DA. The non-motor symptoms of PD, whether related to the disease process or L-DOPA-induced, are not trivial and contribute to worsened disability, impaired quality of life and shortened life expectancy. Therefore, a better understanding of the mechanisms responsible for the non-motor symptoms that accompany the motor problems of PD is called for urgently. A growing body of evidence has established a clear link between protein misfolding and aggregation to cytotoxicity and neurodegenerative conditions. Protein cysteine residues can be viewed as cellular redox sensors. Modification of cysteines by oxidation can change protein conformation in a rapid and reversible way as part of a controlled signaling process. Persistent oxidative stress can overwhelm cellular mechanisms that maintain the delicate balance between protein synthesis and degradation, leading eventually to cellular damage and death. TPH2, in addition to being the initial and rate limiting enzyme in the synthesis of 5HT and a phenotypic marker for 5HT neurons, is a cysteine-rich protein. TPH2 is extremely unstable and can undergo misfolding and aggregation upon mild oxidation, much as is seen with other proteins within DA neurons in PD. We propose that TPH2 targets 5HT neurons for damage as a result PD-related oxidative stress and that L-DOPA can accentuate this process. We will apply a variety of molecular and cell biological approaches along with the use of a unique mouse lacking TPH2 to assess the role of TPH2 in 5HT neuronal compromise seen in PD. PUBLIC HEALTH RELEVANCE: Project Narrative Parkinson's disease (PD) is a progressive neurodegenerative disorder that accounts for significant morbidity and mortality among Veterans and the general population. PD is the seventh leading cause of death in the US. The hallmark motor symptoms of PD can be traced to the loss of dopamine (DA) neurons of the nigrostriatal pathway. However, it is not nearly as widely appreciated that the majority of individuals with PD also suffer from co-morbid neuropsychiatric conditions such as depression, anxiety and sleep disorders. The neurobiological mechanisms responsible for these non-motor symptoms of PD are not known but many indicators point to loss of function in 5HT neurons. It has been suggested that 5HT neurons are severely damaged in PD but very little research has been dedicated to achieving a better understanding of this process. In light of the prevalence of co-morbid neuropsychiatric problems in PD and knowing that these non-motor symptoms contribute to worsened disability, impaired quality of life and shortened life expectancy, it is imperative that we achieve a better understanding of the how the 5HT neuronal system is impacted in this neurodegenerative disorder.

描述（由申请人提供）： 帕金森病（Parkinson's disease，PD）是一种典型的多巴胺（dopamine，DA）神经系统退行性疾病。黑质纹状体DA神经元的进行性丧失逐渐导致严重的运动障碍，其特征在于震颤、僵硬、运动迟缓和平衡受损。PD占退伍军人和普通人群的显著发病率和死亡率。这一点尚未得到广泛认识，但5-羟色胺（5-HT）神经元系统在PD中也受到严重影响。来自患有PD的个体的大脑具有显著较低的5 HT水平、降低的5 HT合成和周转、色氨酸羟化酶（TPH 2）的量的减少和完整的5 HT神经元的数量的损失。鉴于大约80%的PD患者患有共病神经精神疾病，如抑郁症、睡眠障碍、焦虑和痴呆，因此5 HT神经化学功能的下降非常显著。这些疾病中的许多与功能失调的5 HT神经化学有关。左旋多巴是PD的金标准药物治疗。L-DOPA进入大脑，并通过无处不在的L-芳香族氨基酸脱羧酶（L-AADC）转化为DA。这种处理增加了表达L-AADC的所有细胞中的DA，包括DA神经元，如所期望的，以及5 HT和其他神经元中的DA。DA在5 HT神经元内的这种不适当的沉积可以改变它们的神经化学功能，并使它们经受来自L-DOPA和DA的非酶分解产物的升高的氧化应激。PD的非运动症状，无论是与疾病过程相关还是L-DOPA诱导的，都不是微不足道的，并且导致残疾恶化、生活质量受损和预期寿命缩短。因此，更好地了解机制负责伴随运动问题的PD的非运动症状是迫切需要的。越来越多的证据表明，蛋白质错误折叠和聚集与细胞毒性和神经退行性疾病之间存在明确的联系。蛋白质半胱氨酸残基可被视为细胞氧化还原传感器。通过氧化修饰半胱氨酸可以以快速和可逆的方式改变蛋白质构象，作为受控信号传导过程的一部分。持续的氧化应激会压倒维持蛋白质合成和降解之间微妙平衡的细胞机制，最终导致细胞损伤和死亡。TPH 2除了是5 HT合成中的起始酶和限速酶以及5 HT神经元的表型标志物之外，还是富含半胱氨酸的蛋白质。TPH 2是非常不稳定的，并且可以在轻度氧化时发生错误折叠和聚集，就像在PD中DA神经元内的其他蛋白质一样。我们认为TPH 2靶向5 HT神经元，作为PD相关氧化应激的结果，L-DOPA可以加重这一过程。我们将应用各种分子和细胞生物学方法，沿着使用一种独特的缺乏TPH 2的小鼠来评估TPH 2在PD中所见的5 HT神经元损害中的作用。 公共卫生关系： 帕金森病（PD）是一种进行性神经退行性疾病，在退伍军人和普通人群中发病率和死亡率较高。PD是美国第七大死亡原因。PD的标志性运动症状可以追溯到黑质纹状体通路的多巴胺（DA）神经元的丢失。然而，大多数PD患者还患有共病神经精神疾病，如抑郁症，焦虑症和睡眠障碍，这一点并没有得到广泛的认识。负责PD的这些非运动症状的神经生物学机制尚不清楚，但许多指标指向5 HT神经元的功能丧失。有人认为，5 HT神经元在PD中严重受损，但很少有研究致力于更好地理解这一过程。鉴于帕金森病中共病神经精神问题的普遍存在，并且知道这些非运动症状会导致残疾恶化，生活质量受损和预期寿命缩短，因此我们必须更好地了解5 HT神经元系统如何在这种神经退行性疾病中受到影响。