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: 8960358
• 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/8960358
• 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; System; TPH2; Time; Tremor; Tryptophan 5-monooxygenase; Veterans; Wild Type Mouse; abstracting; cysteine rich protein; cytotoxicity; disability; dopaminergic neuron; equilibration disorder; in vivo; loss of function; mortality; motor symptom; neurobiological mechanism; neurochemistry; neuron loss; neuropsychiatry; neurotoxic; nigrostriatal pathway; non-motor symptom; oxidation; phenotypic biomarker; protein aggregation; protein degradation; protein misfolding; response; sensor; signal processing

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.

描述(由申请人提供)： 项目摘要/摘要帕金森病(PD)是多巴胺(DA)神经系统的典型退行性疾病。黑质纹状体DA神经元的进行性丢失逐渐导致以震颤、僵直、运动迟缓和平衡受损为特征的严重运动障碍。帕金森病在退伍军人和普通人群中造成了严重的发病率和死亡率。它没有被广泛认识，但5-羟色胺(5-羟色胺)神经元系统在帕金森病中也受到严重影响。帕金森病患者的大脑5-羟色胺水平显著降低，5-羟色胺合成和周转减少，色氨酸羟化酶(TPH2)含量减少，完整的5-羟色胺神经元数量减少。鉴于大约80%的PD患者患有抑郁症、睡眠障碍、焦虑和痴呆症等共病的神经精神疾病，5HT神经化学功能的下降非常显著。这些情况中的许多与功能失调的5-羟色胺神经化学有关。L多巴是治疗帕金森病的金标准药物。L-多巴进入大脑，并被普遍存在的L芳香氨基酸脱羧酶(L-AADC)转化为DA。这种治疗增加了所有表达L-ADDC的细胞中的DA，包括所需的DA神经元，以及5HT和其他神经元。这种DA在5HT神经元内的不适当沉积可以改变它们的神经化学功能，使它们受到L-多巴和DA的非酶分解产物的氧化应激增加。帕金森病的非运动症状，无论是与疾病进程有关，还是与L-多巴诱发的，都不是微不足道的，都会导致残疾恶化，生活质量下降，预期寿命缩短。因此，迫切需要更好地了解导致帕金森病运动问题的非运动性症状的机制。越来越多的证据已经建立了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的明确联系。蛋白质半胱氨酸残基可视为细胞氧化还原感受器。半胱氨酸的氧化修饰可以快速和可逆地改变蛋白质的构象，这是受控信号过程的一部分。持续的氧化应激可以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。TPH2不仅是合成5-羟色胺的起始酶和限速酶，也是5-羟色胺神经元的表型标志物，也是一种富含半胱氨酸的蛋白质。TPH2极不稳定，在轻度氧化时可能会发生错误折叠和聚集，就像帕金森病患者DA神经元中的其他蛋白质一样。我们认为Tph2靶向帕金森病相关的氧化应激所致的5-羟色胺神经元损伤，而L-多巴可加重这一过程。我们将应用各种分子和细胞生物学方法，以及使用一只独特的缺乏TPH2的小鼠来评估TPH2在帕金森病患者5HT神经元损害中的作用。