Pathway of Protein Misfolding Intiation in vivo

体内蛋白质错误折叠起始途径

• 批准号: 8060245
• 负责人: Janice Villali
• 金额: $ 4.84万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2014-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060245
• 关键词: Age; Alzheimer' s Disease; Appearance; Biogenesis; Bypass; C-terminal; Cell physiology; Complex; Disease; Environment; Event; Frequencies; Goals; Huntington Disease; In Vitro; Link; Mammals; Mining; Modeling; Molecular; Molecular Conformation; Neurodegenerative Disorders; Oligonucleotides; Parkinson Disease; Pathway interactions; Physiological; Prevention; Prion Diseases; Prions; Process; Protein Structure Initiative; Proteins; Quality Control; Research; Saccharomyces cerevisiae; System; Testing; Variant; conformer; in vivo; new therapeutic target; prevent; protein folding; protein misfolding; sup35

DESCRIPTION (provided by applicant): Neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's Diseases and the Transmissible Spongiform Encephalopathies (prion diseases), have been linked to an unusual disease mechanism, in which alternative conformations of cellularly encoded proteins arise and subsequently direct the misfolding of normal conformers of the same protein to a like state. The spontaneous appearance of these disorders has been shown to increase with age, suggesting that cellular mechanisms exist to prevent the pathogenic misfolding pathways from initiating. Although the mechanism of conformational self-replication for these proteins has been well-studied, our mechanistic understanding of the initiation of this state lags far behind. Understanding the pathway that soluble, functional proteins take during this initial misfolding event can provide new therapeutic targets for the prevention and treatment of these diseases. The long-term goal of our research is to understand how the cellular environment regulates protein folding pathways to create both normal physiological and disease states. The objective of this proposal is to determine how a pathway of protein misfolding is initiated in vivo. For these studies, we will exploit the Sup35/[PSI+] prion system of Saccharomyces cerevisiae. While the mechanism by which Sup35 folding switches from the normal ([psi-]) to the misfolded ([PSI+]) pathway is still unknown, this process is dependent on presence of the misfolded form of another prion protein, Rnq1, or on a Sup35 variant with a non-native C- terminal extension. We hypothesize that these factors bypass the rate-limiting step for accumulation of misfolded Sup35, leading to [PSI+] appearance. To test this hypothesis, we will manipulate both the expressing levels of key players in the Sup35 misfolding pathway and the Sup35 sequence and link changes in the frequency of [PSI+] appearance to changes in the biogenesis of the Sup35 protein in vivo. By developing an understanding of how protein folding pathways can be modulated by their cellular environment, we will begin to reveal the molecular contributions of these processes to both normal cellular physiology and to the appearance and spread of diseases. PUBLIC HEALTH RELEVANCE: Severe neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's Diseases as well as the Transmissible Spongiform Encephalopathies (prion diseases) have been linked to an unusual disease mechanism, in which alternative conformations of normal cellularly encoded proteins arise and subsequently direct the misfolding of normal conformers of the same protein to a like state. Understanding the pathway that soluble, functional proteins take during the initial misfolding event can provide new therapeutic targets for the prevention and treatment of these diseases.

描述（由申请人提供）：神经退行性疾病，包括阿尔茨海默氏症，亨廷顿和帕金森氏疾病以及易传播的海绵状脑病（prion疾病），已与不寻常的疾病机制联系起来，在这种机制中，类似于细胞的构造的构造的构造构成了构造的构造，并随后构成了综合的原始构型，并随后构成了该疾病的构造，并随后构成了该疾病的疾病，并随着疾病的范围，并随后疾病的疾病是综合的。 状态。这些疾病的自发外观已被证明随着年龄的增长而增加，这表明存在细胞机制以防止致病性错误折叠途径引发。尽管对这些蛋白质的构象自我复制的机制进行了充分研究，但我们对这种状态起始的机械理解远远落后。了解最初的错误折叠事件中可溶性功能蛋白采取的途径可以为预防和治疗这些疾病提供新的治疗靶标。我们研究的长期目标是了解细胞环境如何调节蛋白质折叠途径以创建正常的生理和疾病状态。该建议的目的是确定如何在体内启动蛋白质错误折叠的途径。对于这些研究，我们将利用酿酒酵母的Sup35/[PSI+] prion系统。尽管SUP35折叠从正常（[PSI-]）转换为错误折叠（[PSI+]）途径的机制仍然未知，但此过程取决于另一种prion蛋白RNQ1的错误折叠形式的存在，或在具有非本性C-终端扩展的SUP35变量上。我们假设这些因素绕过了错误折叠的SUP35的限制步骤，从而导致[PSI+]出现。为了检验这一假设，我们将操纵SUP35错误折叠途径中的主要参与者的表达水平和SUP35序列以及[PSI+]外观频率的链接变化与体内Sup35蛋白质的生物发生变化。通过了解如何通过其细胞环境调节蛋白质折叠途径，我们将开始揭示这些过程对正常细胞生理学以及疾病的外观和扩散的分子贡献。 公共卫生相关性：包括阿尔茨海默氏症，亨廷顿和帕金森氏疾病在内的严重神经退行性疾病以及可传播的海绵状脑病（prion疾病）与不寻常的疾病机制有关 状态。了解最初的错误折叠事件中可溶性功能蛋白采取的途径可以为预防和治疗这些疾病提供新的治疗靶标。