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

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。 公共卫生相关性： 项目简介帕金森病(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造成显著的发病率和死亡率。帕金森病是美国第七大死因。帕金森病的显著运动症状可追溯到黑质纹状体通路的多巴胺(DA)神经元的丢失。然而，人们并没有广泛认识到，大多数帕金森氏症患者也患有抑郁症、焦虑和睡眠障碍等共病的神经精神疾病。帕金森病的这些非运动性症状的神经生物学机制尚不清楚，但许多指标表明5-羟色胺神经元功能丧失。有研究表明，帕金森病患者5-羟色胺神经元受到严重损害，但致力于更好地了解这一过程的研究很少。鉴于帕金森病合并神经精神问题的普遍存在，以及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，我们必须更好地了解5HT神经系统在这种神经退行性疾病中是如何受到影响的。

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.