Protection against Alzheimer's Disease proteins by novel ubiquitin processes

通过新型泛素过程预防阿尔茨海默病蛋白

• 批准号: 10283294
• 负责人: Sokol Todi
• 金额: $ 23.65万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283294
• 关键词: Adopted; Age; Alzheimer' s Disease; Amyloid; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Attention; Biochemical; Biological Process; Biology; Brain; Cell physiology; Cells; Cessation of life; Cleaved cell; Clinic; Complex; Data; Degradation Pathway; Development; Disease; Drosophila eye; Drosophila genus; Electroretinography; Etiology; Eye; Family; Funding; Grant; Health; Homeostasis; Human; Laboratories; Lead; Length; Light; Link; Longevity; Machado-Joseph Disease; Mass Spectrum Analysis; Modification; Molecular Conformation; Nerve Degeneration; Nervous system structure; Neuronal Dysfunction; Neurons; Pathologic; Pathway interactions; Patients; Performance; Polyubiquitin; Population; Process; Property; Proteins; Publishing; Role; Stress; Structure; Testing; Toxic effect; Transgenic Organisms; Ubiquitin; Ubiquitination; Work; base; cell growth regulation; cell motility; fighting; fly; in vivo; insight; interest; misfolded protein; multicatalytic endopeptidase complex; mutant; nervous system disorder; neurotoxic; novel; polyglutamine; premature; protein degradation; protein folding; protein misfolding; response; tau Proteins; tau mutation

ABSTRACT Alzheimer's Disease (AD) is highly prevalent, incurable and will continue to grow in impact and reach as our population's age increases. In AD, Aβ and Tau proteins convert from normal protein folding into toxic amyloid conformations. These processes cause neuronal dysfunction and, ultimately, death. Ground-breaking work has been conducted to understand how and why proteins such as Aβ and Tau become toxic and cause neurodegeneration. Still, the etiology of AD remains unclear and solutions for it in the clinic presently elude us. Our laboratory has a long-standing interest in diseases of the nervous system caused by proteins harboring abnormally elongated polyglutamine repeats. Among these diseases is Spinocerebellar Ataxia Type 3 (SCA3), the focus of the currently funded grant, R01 NS086778. In recent work with the causative protein in SCA3 we found that unique processes that involve the small modifier protein, ubiquitin, have suppressive effects. Ubiquitin is best known for its role in targeting proteins for degradation by the proteasome. But, this small protein has many other functions in the cell. Ubiquitination leads to various substrates and mod- ifications, among which are poly-ubiquitin chains that are not attached onto another protein, referred to as unanchored or free chains. We have found that unanchored chains suppress toxicity from polyg- lutamine species, such as the SCA3 protein. Through this application, we propose to extend these observations by investigating the role of free ubiquitin chains in the cellular response against Aβ and Tau in AD.

摘要 阿尔茨海默病(AD)非常普遍，无法治愈，其影响和影响范围将继续扩大 随着我们人口年龄的增长。在AD中，Aβ和Tau蛋白从正常的蛋白质折叠转变为 有毒的淀粉样蛋白构象。这些过程会导致神经元功能障碍，最终导致死亡。 已经进行了开创性的工作来了解Aβ和Tau等蛋白质是如何以及为什么 变得有毒并导致神经退化。尽管如此，AD的病因和解决方案仍不清楚 因为它在诊所里目前还不为我们所知。 我们的实验室长期以来一直对蛋白质引起的神经系统疾病感兴趣。 含有异常延长的聚谷氨酰胺重复序列。脊髓小脑是这些疾病中的一种 共济失调3型(SCA3)，目前资助的重点，R01 NS086778。在最近与 在SCA3中的致病蛋白我们发现涉及小修饰蛋白的独特过程， 泛素，具有抑制作用。 泛素最为人所知的是它在蛋白酶体降解蛋白质方面的作用。但是，这个 小蛋白在细胞中还有许多其他功能。泛素化导致不同的底物和MOD- 结果，其中包括没有连接到另一种蛋白质上的多泛素链，参考 不固定的或自由的链条。我们发现，未锚定的链可以抑制多聚糖的毒性。 谷氨酰胺种类，如SCA3蛋白。通过此应用程序，我们建议扩展这些 通过研究游离泛素链在细胞对β和 公元一年的陶氏。