Misfolding and aggregation of polyglutamine sequences in neurodegenerative diseases

神经退行性疾病中多聚谷氨酰胺序列的错误折叠和聚集

• 批准号: 9036812
• 负责人: Samuel A Kotler
• 金额: --
• 依托单位: U.S. NATIONAL INST DIABETES/DIGST/KIDNEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2018-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036812
• 关键词: Adenine; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloidosis; Animals; Biochemical; Calorimetry; Cell Nucleus; Cell physiology; Characteristics; Clinical; Contracts; Cytosine; Data; Development; Disease; Disease Progression; Electron Spin Resonance Spectroscopy; Exons; Fluorescence Spectroscopy; Genes; Goals; Guanine; Homeostasis; Huntington Disease; Huntington gene; Investigation; Kinetics; Knowledge; Lead; Length; Localized Disease; Mediating; Methodology; Methods; Molecular; Molecular Chaperones; Mutate; Mutation; N-terminal; NMR Spectroscopy; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Onset of illness; Outcome; Parkinson Disease; Pathogenesis; Peptide Fragments; Peptides; Play; Process; Property; Protein Fragment; Proteins; Proteolysis; Published Comment; Quality Control; Resistance; Resolution; Role; Structure; Syndrome; System; Therapeutic; Tissues; Toxic effect; Trinucleotide Repeat Expansion; Work; amyloid formation; beta pleated sheet; biophysical techniques; conformer; insight; interest; mitochondrial dysfunction; mutant; nervous system disorder; neurotoxicity; neutrophil; overexpression; polyglutamine; protein aggregate; protein folding; protein misfolding; public health relevance; self assembly; therapeutic development; Adenine; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyloid; Amyloidosis; Animals; Biochemical; Calorimetry; Cell Nucleus; Cell physiology; Characteristics; Clinical; Contracts; Cytosine; Data; Development; Disease; Disease Progression; Electron Spin Resonance Spectroscopy; Exons; Fluorescence Spectroscopy; Genes; Goals; Guanine; Homeostasis; Huntington Disease; Huntington gene; Investigation; Kinetics; Knowledge; Lead; Length; Localized Disease; Mediating; Methodology; Methods; Molecular; Molecular Chaperones; Mutate; Mutation; N-terminal; NMR Spectroscopy; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Onset of illness; Outcome; Parkinson Disease; Pathogenesis; Peptide Fragments; Peptides; Play; Process; Property; Protein Fragment; Proteins; Proteolysis; Published Comment; Quality Control; Resistance; Resolution; Role; Structure; Syndrome; System; Therapeutic; Tissues; Toxic effect; Trinucleotide Repeat Expansion; Work; amyloid formation; beta pleated sheet; biophysical techniques; conformer; insight; interest; mitochondrial dysfunction; mutant; nervous system disorder; neurotoxicity; neutrophil; overexpression; polyglutamine; protein aggregate; protein folding; protein misfolding; public health relevance; self assembly; therapeutic development

 DESCRIPTION (provided by applicant): The formation of accumulated, abnormally folded proteins is associated with more than twenty different clinical syndromes, each of which is associated with a distinct `misfolding' protein. These misfolded proteins aggregate and form the hallmarks of many neurodegenerative diseases, termed amyloids. Amyloid formation is associated with neurodegenerative disseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as localized diseases such as Type II Diabetes. Of the amyloid-related diseases, polyglutamine (polyQ) diseases represent a set of heritable neurological disorders, comprising at least nine diseases. In polyQ diseases like Huntington's disease (HD), our knowledge of how and why an expanded tract of polyQ leads to aggregation and amyloid formation is largely hampered by the fact that there is little high-resolution structural and dynamic insight into this process. Furthermore, the ability of a polyQ protein misfolded species to engage in aberrant protein interactions has become increasingly studied. Particularly, the interactions of polyQ proteins with molecular chaperones and their resistance to proteolysis are poorly understood. Challenges posed by polyQ proteins are manifold and, therefore, new biochemical and biophysical approaches developed to tackle such problems would greatly aid our understanding of polyQ diseases. To accomplish this goal, this application seeks to further investigate the aggregative properties of polyQ proteins at high-resolution, namely the N- terminal fragment of the huntingtin protein (implicated in the progression of HD), by using by nuclear magnetic resonance (NMR) spectroscopy. Newly developed NMR methods, such as dark-state exchange saturation transfer (DEST) and lifetime line broadening, offer the capability to achieve atomic resolution on the dynamic exchange occurring in the self-assembly of polyQ proteins, in addition to their interactions with molecular chaperones such as Hsp70 and Hsp40. While this proposal will focus on the development and application of new NMR methodologies to such challenging systems, the study will be extended for investigation using a variety of other biophysical techniques, including electron paramagnetic resonance (EPR), fluorescence spectroscopy, and calorimetry. The outcome of the proposed studies on amyloid formation by polyQ proteins will significantly advance our understanding of HD and other polyQ diseases, in general, by achieving structural and dynamic insights with atomic-level resolution and will aid in the development of therapeutic strategies for such diseases.

 描述（由适用提供）：累积，绝对折叠蛋白的形成与二十多种不同的临床综合征有关，每种综合症都与独特的“错误折叠”蛋白有关。这些错误折叠的蛋白质聚集并形成了许多神经退行性疾病的标志，称为淀粉样蛋白。淀粉样蛋白形成与神经退行性溶液（如阿尔茨海默氏症，帕金森氏病和亨廷顿氏病）以及局部疾病（如II型糖尿病）有关。在淀粉样蛋白相关的疾病中，聚谷氨酰胺（PolyQ）疾病代表一组可遗传的神经系统疾病，至少完成了9种疾病。在诸如亨廷顿氏病（HD）之类的PolyQ疾病中，我们对PolyQ扩展的方式以及为什么会导致聚集和淀粉样蛋白形成的了解，这在很大程度上受到了这一过程的高分辨率结构和动态洞察力的影响。此外，多克蛋白错误折叠物种从事异常蛋白质相互作用的能力变得越来越多地研究。特别是，Polyq蛋白与分子伴侣的相互作用及其对蛋白解的耐药性知之甚少。 PolyQ蛋白提出的挑战是多种多样的，因此，为解决此类问题而开发的新生化和生物物理方法将极大地帮助我们对PolyQ疾病的理解。为了实现这一目标，该应用程序旨在进一步研究PolyQ蛋白在高分辨率的总体特性，即通过核磁共振（NMR）光谱法使用亨廷汀蛋白的N末端片段（在HD的进展中暗示）。新开发的NMR方法，例如黑态交换满意度转移（DEST）和终生线扩展，除了它们与HSP70和HSP40等分子链酮的相互作用外，还可以在PolyQ蛋白自组装中实现原子分辨率。尽管该提案将集中于新的NMR方法在此类挑战系统中的开发和应用，但该研究将使用各种其他生物物理技术进行投资，包括电子顺磁共振（EPR），荧光光谱和量热法。通常，通过PolyQ蛋白对淀粉样蛋白形成的拟议研究的结果将显着提高我们对HD和其他PolyQ疾病的理解，通常通过实现原子级分辨率来实现结构和动态见解，并将有助于开发此类疾病的治疗策略。