Defining reaction mechanisms of threshold phenomena in conformational disease

描述（由申请人提供）：涉及正常蛋白质折叠破坏的疾病称为“构象疾病”。“蛋白质由于突变、压力或随机事件而发生错误折叠。错误折叠的蛋白质形成聚集体并影响天然（旁观者）蛋白质的形式和功能。众所周知，这些对蛋白质稳态的破坏与神经系统疾病和朊病毒疾病有关。然而，鲜为人知的是蛋白质错误折叠和某些糖尿病表型之间的关联。蛋白质错误折叠和聚集对天然蛋白质形成和产生的影响的机制还没有很好地理解。在构象疾病中经常观察到的一种现象是阈值现象。细胞聚集水平不知何故被驱动越过从无毒到有毒的阈值。我们的长期目标是阐明聚集倾向性错误折叠蛋白对旁观者蛋白发育的影响机制。我们的近期目标是进一步描述在构象疾病中观察到的阈值现象所需的条件。在这里，我们提出了一个一般的数学模型，描述错误折叠的蛋白质对旁观者蛋白质生产的影响和存在的阈值现象的条件的初步数据。两个目标将研究阈值现象如何在构象疾病中表现出来：具体目标1：确定负责构象疾病中阈值现象表现的关键反应基序。具体目标2：评估蛋白质通量对构象疾病中天然蛋白质消失的动力学行为的影响。 公共卫生相关性：细胞质量控制过程的中断可能导致错误折叠蛋白质的错误管理，导致有毒蛋白质聚集和疾病。错误折叠蛋白质和相关聚集的水平升高与多种疾病如阿尔茨海默病、腓骨肌萎缩症和糖尿病有关。了解蛋白质错误折叠和聚集背后的详细机制将有助于深入了解细胞质量控制以及蛋白质错误折叠疾病患者的潜在治疗方法。

DESCRIPTION (provided by applicant): Diseases involving disruptions in proper protein folding are termed "conformational diseases." Proteins undergo misfolding due to mutation, stress or stochastic events. Misfolded proteins form aggregates and impact native (bystander) protein form and function. These disruptions to protein homeostasis are well known to be associated with neurological and prion diseases. Less known, however is the association between protein misfolding and certain diabetic phenotypes. The mechanisms of the impact of protein misfolding and aggregation on native protein formation and production are not well understood. One often observed occurrence in conformational diseases is a threshold phenomenon. Cellular aggregate levels are somehow driven across a threshold from nontoxic to toxic. Our long range goal is to elucidate the mechanism(s) of the impact of aggregate prone misfolded protein on bystander protein development. Our immediate goal is to further describe the conditions necessary for the threshold phenomenon observed in conformational diseases. Here, we present preliminary data of a general mathematical model describing the impact of misfolded protein on bystander protein production and the conditions for existence of a threshold phenomenon. Two aims will examine how the threshold phenomenon manifests in conformational diseases: Specific Aim 1: Identify the key reaction motifs responsible for the manifestation of threshold phenomena in conformational diseases. Specific Aim 2: Evaluate the effects of protein fluxes on the dynamical behavior of native protein disappearance in conformational diseases. PUBLIC HEALTH RELEVANCE: A disruption in cellular quality control processes can lead to the mismanagement of misfolded proteins, resulting in toxic protein aggregation and disease. Elevated levels of misfolded protein and associated aggregation are implicated in a variety of diseases such as Alzheimer's, Charcot-Marie-Tooth and diabetes mellitus. Understanding the detailed mechanisms behind protein misfolding and aggregation will lend insight into cellular quality control as well as into potential treatments for patients with protein misfolding diseases.