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/摘要帕金森氏病（PD）是多巴胺（DA）神经元系统的原型退化性疾病。黑质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，僵化，头肌障碍和平衡受损。 PD解释了退伍军人和普通人群的显着发病率和死亡率。它并没有得到广泛的欣赏，但是5-羟色胺（5HT）神经元系统在PD中也受到严重影响。来自PD个体的大脑的5HT水平明显降低，5HT合成和周转率，色氨酸羟化酶量减少（TPH2）（TPH2）的量减少以及完整的5HT神经元数量的损失。鉴于大约80％的PD患者患有抑郁症，睡眠障碍，焦虑症和痴呆症，大约80％的PD患者患有5HT神经化学功能的下降非常重要。这些条件中的许多与功能失调的5HT神经化学有关。 L-DOPA是PD的金标准药物疗法。 L-DOPA进入大脑，并通过无处不在的L-芳基氨基酸脱羧酶（L-AADC）转化为DA。这种处理均在所有表达L-AADC的细胞中增加了DA，并根据需要以及5HT和其他神经元中的DA神经元包括DA神经元。 DA在5HT神经元中的这种不适当的沉积可以改变其神经化学功能，并使L-DOPA和DA的非酶促分解产物产生增强的氧化应激。 PD的非运动症状，无论是与疾病过程有关还是L-DOPA引起的，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，对PD运动问题伴随非运动症状的机制有了更好的理解。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条件之间的明显联系。蛋白质半胱氨酸残基可以看作是细胞氧化还原传感器。通过氧化对半胱氨酸的修饰可以作为受控信号过程的一部分以快速而可逆的方式改变蛋白质构象。持续的氧化应激会淹没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除了是5HT合成和5HT神经元的表型标记中的初始和速率限制酶外，还具有富含半胱氨酸的蛋白质。 TPH2非常不稳定，并且在轻度氧化后可能会出现错误折叠和聚集，就像PD中DA神经元内的其他蛋白质一样。我们提出，TPH2靶向5HT神经元造成损伤，因此PD相关的氧化应激，L-DOPA可以强调这一过程。我们将应用各种分子和细胞生物学方法，以及使用缺乏TPH2的独特小鼠来评估TPH2在PD中看到的TPH2在5HT神经元妥协中的作用。