Structural Characterization of Amyloid Fibrils Using Deep UV Raman Spectroscopy

使用深紫外拉曼光谱法表征淀粉样原纤维的结构

• 批准号: 8657972
• 负责人: IGOR K LEDNEV
• 金额: $ 20.33万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657972
• 关键词: Adopted; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloidosis; Appearance; Complement; Creutzfeldt-Jakob Syndrome; Deuterium; Diagnostic radiologic examination; Disease; Employee Strikes; Familial Amyloid Neuropathies; Future; Genetic Polymorphism; Goals; HIV; Heterogeneity; Huntington Disease; Hydrogen; Hydrogen Bonding; In Vitro; Isotope Labeling; Kinetics; Knowledge; Label; Laboratories; Length; Literature; Methodology; Methods; Modeling; Molecular Conformation; Morphology; Nature; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Parkinson Disease; Patients; Peptide Fragments; Peptides; Phosphoric Monoester Hydrolases; Prion Diseases; Prions; Process; Property; Prostatic; Protein Precursors; Proteins; Raman Spectrum Analysis; Reaction; Reporting; Roentgen Rays; Role; Seminal fluid; Sexual Transmission; Solutions; Structural Models; Structure; Symptoms; System; Testing; Therapeutic; Time; Toxic effect; Variant; Vertebral column; X-Ray Crystallography; amyloid fibril formation; base; comparative; design; improved; in vivo; molecular dynamics; neutrophil; novel; particle; polypeptide; protein aggregate; protein misfolding; public health relevance; small molecule; solid state; solid state nuclear magnetic resonance; structural biology; therapeutic development; tool; ultraviolet

DESCRIPTION (provided by applicant): Amyloid fibrils are associated with numerous debilitating diseases such as Alzheimer's disease, Parkinson's disease, Huntington's diseases, prion disease, familial amyloid polyneuropathy, senile systemic amyloidosis and type II diabetes, etc. The rational design of successful therapeutic strategies calls for detailed structural characterization of amyloid fibrils. Solid-state NMR and X-ray microcrystallography applied to short peptide fragments of amyloidogenic proteins have contributed greatly to our knowledge about the fibril core structure. The main goal of this project is to extend our understanding of the amyloid fibril structure by utilizing deep ultraviolet resonance Raman spectroscopy combined with hydrogen-deuterium exchange. This new method, recently pioneered in our laboratory, does not require isotope labeling and creates the opportunity for bridging the gap between our extended knowledge in the structural variations of model short peptide microcrystals and the core structure of amyloid fibrils prepared from entire proteins. We will determine and classify the core structure of amyloid fibrils prepared from full-length proteins. It has been postulated that differences in infectivity of prion protein aggregates, and related differences in the apparent symptoms of Creutzfeldt-Jakob disease patients, are possible due to amyloid polymorphism. Small molecules could potentially manipulate aggregate morphology and provide the basis for therapeutic approaches to suppress the formation of toxic aggregates. Therefore, it is critical to (i) have a robust method for structural characterization of polymorphs, (ii) understand the nature of amyloid polymorphs and their toxicity, and (iii) eventually, be able to control (suppress) the formation of toxic polymorphs. We will test alternative hypothesis concerning the level of structure at which functional polymorphisms are realized. When fully developed, in future studies, the proposed approach will make possible the comparative structural characterization of in vivo and in vitro amyloid fibrils. This will bridge the gap between in vivo and in vitro studies of neurodegenerative diseases. In particular, the method will provide unique information revealing the structural determinants of infectious and non-infectious amyloids.

描述（申请人提供）：淀粉样原纤维与多种衰弱性疾病有关，如阿尔茨海默病、帕金森病、亨廷顿舞蹈病、朊病毒病、家族性淀粉样多发性神经病、老年系统性淀粉样变性和II型糖尿病等。成功治疗策略的合理设计需要淀粉样原纤维的详细结构表征。将固态核磁共振和 X 射线微晶体学应用于淀粉样蛋白的短肽片段，极大地增进了我们对原纤维核心结构的了解。该项目的主要目标是利用深紫外共振拉曼光谱结合氢-氘交换来扩展我们对淀粉样蛋白原纤维结构的理解。这种新方法是我们实验室最近首创的，不需要同位素标记，并为弥合我们对模型短肽微晶结构变化的广泛知识与从整个蛋白质制备的淀粉样原纤维的核心结构之间的差距创造了机会。我们将确定并分类由全长蛋白质制备的淀粉样原纤维的核心结构。据推测，朊病毒蛋白聚集体的感染性差异以及克雅氏病患者的明显症状的相关差异可能是由于淀粉样蛋白多态性造成的。小分子可能会操纵聚集体形态，并为抑制有毒聚集体形成的治疗方法提供基础。因此，至关重要的是（i）拥有可靠的多晶型物结构表征方法，（ii）了解淀粉样蛋白多晶型物的性质及其毒性，以及（iii）最终能够控制（抑制）有毒多晶型物的形成。我们将测试关于实现功能多态性的结构水平的替代假设。当在未来的研究中得到充分发展时，所提出的方法将使体内和体外淀粉样原纤维的比较结构表征成为可能。这将弥补神经退行性疾病的体内和体外研究之间的差距。特别是，该方法将提供揭示感染性和非感染性淀粉样蛋白的结构决定因素的独特信息。

项目成果

Surface characterization of insulin protofilaments and fibril polymorphs using tip-enhanced Raman spectroscopy (TERS).

使用尖端增强拉曼光谱 (TERS) 对胰岛素原丝和原纤维多晶型物进行表面表征。

• DOI: 10.1016/j.bpj.2013.10.040
• 发表时间: 2014-01-07
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: D. Kurouski;Tanja Deckert;V. Deckert;I. Lednev
• 通讯作者: I. Lednev

Amide I vibrational mode suppression in surface (SERS) and tip (TERS) enhanced Raman spectra of protein specimens.

表面 (SERS) 和尖端 (TERS) 的酰胺 I 振动模式抑制增强了蛋白质样本的拉曼光谱。

• DOI: 10.1039/c2an36478f
• 发表时间: 2013-03-21
• 期刊: The Analyst
• 作者: Kurouski D;Postiglione T;Deckert-Gaudig T;Deckert V;Lednev IK
• 通讯作者: Lednev IK

Raman spectroscopy of blood serum for Alzheimer's disease diagnostics: specificity relative to other types of dementia.

用于阿尔茨海默病诊断的血清拉曼光谱：相对于其他类型痴呆的特异性。

• 发表时间: 2015-07
• 作者: Ryzhikova, Elena;Kazakov, Oleksandr;Halamkova, Lenka;Celmins, Dzintra;Malone, Paula;Molho, Eric;Zimmerman, Earl A;Lednev, Igor K
• 通讯作者: Lednev, Igor K

Polarized Raman Spectroscopy for Determining the Orientation of di-D-phenylalanine Molecules in a Nanotube.

用于确定纳米管中二-D-苯丙氨酸分子取向的偏振拉曼光谱。

• DOI: 10.1002/jrs.4884
• 发表时间: 2016-09
• 期刊: Journal of Raman spectroscopy : JRS
• 作者: Sereda, Valentin;Ralbovsky, Nicole M.;Vasudev, Milana C.;Naik, Rajesh R.;Lednev, Igor K.
• 通讯作者: Lednev, Igor K.

Origin of enhanced VCD in amyloid fibril spectra: Effect of deuteriation and pH.

淀粉样原纤维光谱中增强 VCD 的起源：氘化和 pH 的影响。

• 发表时间: 2017-09
• 影响因子: 2
• 作者: Pazderková, Markéta;Pazderka, Tomáš;Shanmugasundaram, Maruda;Dukor, Rina K;Lednev, Igor K;Nafie, Laurence A
• 通讯作者: Nafie, Laurence A