Enhancement of Proteasome Activity for the Treatment of Neurological Disorders

增强蛋白酶体活性治疗神经系统疾病

• 批准号: 8243424
• 负责人: Scott Michael Wilson
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243424
• 关键词: Alzheimer' s Disease; Animal Model; Cell Nucleus; Cells; Chronic; Cytosol; Deubiquitinating Enzyme; Disease; Effectiveness; Frontotemporal Dementia; Genetic; Huntington Disease; Hydrolase; Lead; MJD1 protein; Medical; Mus; Mutant Strains Mice; Neurons; Parkinson Disease; Patients; Production; Proteasome Inhibitor; Proteins; Side; Spinocerebellar Ataxias; System; Transgenes; Ubiquitin; Work; cancer therapy; design; efficacy testing; improved; inhibitor/antagonist; intraperitoneal; mouse model; multicatalytic endopeptidase complex; mutant; nervous system disorder; novel; novel strategies; novel therapeutic intervention; protein TDP-43; protein aggregate; protein degradation; protein expression; protein misfolding; synuclein; tau Proteins; tau aggregation

DESCRIPTION (provided by applicant): While proteasome inhibitors are an effective cancer treatment option, the idea of accelerating the activity of the proteasome for medical purposes represents a novel treatment option for neurological disorders where harmful proteins accumulate and cause disease. Chronic neurological diseases such as Parkinson's, Alzheimer's, Huntington's, Frontotemporal dementia and Spinocerebellar ataxias are characterized by the presence of ubiquitinated protein aggregates and reduced proteasome function. Therefore, while these mutant proteins can be targeted for proteasomal degradation, they are not effectively eliminated by the ubiquitin proteasome system. We recently determined that either genetic or pharmacological inhibition of the ubiquitin hydrolase activity of Usp14 is sufficient to accelerate protein degradation by the proteasome. The levels of several proteins, including tau, TDP-43 and ataxin-3, were significantly decreased following the inhibition of Usp14's ubiquitin- hydrolase activity, indicating that Usp14 can function as an inhibitor of the proteasome. Our working hypothesis is that Usp14 functions to edit the ubiquitin side chains of proteins prior to their commitment to proteasomal degradation, resulting in release of the substrate from the proteasome. The focus of this proposal is to determine if loss of Usp14's ubiquitin hydrolase-activity can reduce the levels of aggregate- prone proteins produced in animal models of Huntington's disease, Frontotemporal dementia and Parkinson's disease. This novel approach to enhancing proteasome function for the clearance of aggregate- prone proteins may lead to a powerful new treatment option for patients suffering from chronic neurological diseases. PUBLIC HEALTH RELEVANCE: The ubiquitin proteasome system functions to remove damaged and misfolded proteins within cells. Since many chronic neurological disorders show impaired protein degradation and protein accumulation, strategies designed to enhance proteasome activity offer provide a novel therapeutic intervention for the clearance of toxic proteins.

描述(申请人提供)：虽然蛋白酶体抑制剂是一种有效的癌症治疗选择，但出于医疗目的加速蛋白酶体活性的想法代表了一种新的治疗方案，用于治疗有害蛋白质积累并导致疾病的神经疾病。帕金森氏症、阿尔茨海默氏症、亨廷顿氏症、额颞叶痴呆和脊髓小脑性共济失调等慢性神经系统疾病的特点是泛素化的蛋白聚集体和蛋白酶体功能降低。因此，虽然这些突变蛋白可以被蛋白酶体降解，但它们不能被泛素蛋白酶体系统有效地消除。我们最近确定，对USP14泛素水解酶活性的遗传或药物抑制足以加速蛋白酶体的蛋白质降解。抑制USP14‘S泛素水解酶活性后，tau、Tdp-43和ataxin-3等蛋白的表达水平显著降低，表明USP14可以作为蛋白酶体的抑制因子。我们的工作假设是，Usp14的功能是在蛋白质泛素侧链参与蛋白酶体降解之前编辑它们，导致底物从蛋白酶体中释放出来。这项建议的重点是确定USP14的S泛素水解酶活性的丧失是否可以减少亨廷顿病、额颞痴呆和帕金森病动物模型中产生的聚集倾向蛋白的水平。这种增强蛋白酶体功能以清除聚集倾向蛋白的新方法可能会为患有慢性神经疾病的患者带来一种强大的新治疗选择。 与公共健康相关：泛素蛋白酶体系统的功能是去除细胞内受损和错误折叠的蛋白质。由于许多慢性神经系统疾病表现为蛋白质降解和蛋白质积累受损，因此旨在增强蛋白酶体活性的策略为有毒蛋白质的清除提供了一种新的治疗干预措施。