Optimizing and defining the mechanism of alpha-synuclein disaggregation by Hsp104

优化和定义 Hsp104 α-突触核蛋白解聚机制

• 批准号: 8514957
• 负责人: Morgan DeSantis
• 金额: $ 0.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514957
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Affect; Age of Onset; Alzheimer' s Disease; Amyloid; Amyloid fibers; Binding; Bradykinesia; Brain; Calorimetry; Characteristics; Collaborations; Couples; Data; Deterioration; Disease; Dyes; Effectiveness; Electron Microscopy; Ensure; Fiber; Goals; Hydrolysis; In Vitro; Individual; Lewy Bodies; Link; Mediating; Missense Mutation; Modeling; Molecular Conformation; Monitor; Movement Disorders; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; North America; Nucleotides; Parkinson Disease; Patients; Peptides; Positioning Attribute; Protein Conformation; Proteins; Rattus; Resistance; Role; Sedimentation process; Severities; Shapes; Structure; Substantia nigra structure; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Titrations; Toxic effect; Tremor; Yeasts; alpha synuclein; amyloid formation; amyloid structure; base; brain tissue; dopaminergic neuron; effective therapy; mutant; pars compacta; protein aggregate; protein aggregation; protein misfolding; protein structure; research study; stoichiometry; synuclein; therapeutic target; translocase; yeast protein

DESCRIPTION (provided by applicant): Misfolding and aggregation of the protein ?-synuclein (? -syn) is associated with Parkinson's Disease (PD), which is a devastating neurodegenerative movement disorder. In PD, ? -syn misfolds into an aberrant protein conformation, termed amyloid, which is highly stable, possesses a characteristic cross-?? structure, and is largely viewed to be an intractable condition. There is evidence that pre- amyloid oligomers of ? -syn possess greater toxicity than the fibers themselves. Furthermore, certain rare mutations of ? -syn are associated with familial forms of PD and often result in a decreased age of onset and increased severity of symptoms. These mutants have been shown to increase propensity of ? -syn aggregation or to increase the concentration of the pre-amyloid oligomers. A remarkable yeast protein, Hsp104, has been shown to ameliorate symptoms of ? -syn aggregation in a rat model of PD by disaggregating the ? -syn fibers and oligomers. However, high concentrations of Hsp104 were required to observe disaggregation, which reduces the effectiveness of this potential PD therapeutic. Additionally, it is not clear how Hsp104 is able to remodel ? -syn fibers and oligomers, which obscures ways in which this protein may be further developed to treat PD. We have isolated an Hsp104 mutant with even greater potency towards ? -syn fibers, which gives us confidence that Hsp104 will be eventually become a viable PD treatment. The goal of this proposal is to optimize Hsp104 for even higher anti-?? -syn fiber and oligomer activity. We plan on targeting both wild-type and disease associated mutants of ? -syn to ensure that Hsp104 can be used to treat all cases of PD. We also aim to understand the mechanism of Hsp104 disaggregation of ? -syn fibers and oligomers in order to facilitate even further optimization of Hsp104 as a PD therapeutic.

性状（由申请方提供）：蛋白质的错误折叠和聚集？-突触核蛋白（？-syn）与帕金森病（PD）相关，帕金森病是一种破坏性的神经退行性运动障碍。在警局，？-syn错误折叠成一种异常的蛋白质构象，称为淀粉样蛋白，它是高度稳定的，具有特征性的交叉？结构，并在很大程度上被视为一个棘手的条件。有证据表明前淀粉样蛋白低聚物？-syn具有比纤维本身更大的毒性。此外，某些罕见的突变？-syn与家族性PD相关，通常导致发病年龄降低和症状严重程度增加。这些突变体已被证明增加的倾向？- 顺式聚集或增加前淀粉样蛋白低聚物的浓度。一个显着的酵母蛋白，热休克蛋白104，已被证明可以改善症状？-syn聚集在大鼠模型的PD通过解聚？- 合成纤维和低聚物。然而，需要高浓度的Hsp 104来观察解聚，这降低了这种潜在的PD治疗剂的有效性。目前尚不清楚HSP 104是如何被改造的。-syn纤维 和低聚物，这掩盖了进一步开发这种蛋白质以治疗PD的方法。我们已经分离出一种Hsp 104突变体，其对？-syn纤维，这给了我们信心，热休克蛋白104将最终成为一个可行的PD治疗。该提案的目标是优化HSP 104，以获得更高的抗？- 合成纤维和低聚物活性。我们计划针对野生型和疾病相关的突变体？-syn以确保Hsp 104可用于治疗所有PD病例。我们还旨在了解热休克蛋白104解聚的机制？- 合成纤维和寡聚物，以促进Hsp 104作为PD治疗剂的进一步优化。