Enhancement of Proteasome Activity for the Treatment of Neurological Disorders

描述（由申请人提供）：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有害蛋白质积累并导致疾病的神经系统疾病的新治疗选择。慢性神经系统疾病如帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、额颞叶痴呆和脊髓小脑共济失调的特征在于存在泛素化蛋白质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靶向蛋白酶体降解，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，无论是遗传或药理学抑制泛素水解酶活性的Usp 14是足以加速蛋白质降解的蛋白酶体。在抑制Usp 14的泛素水解酶活性后，包括tau、TDP-43和共济失调蛋白-3在内的几种蛋白质的水平显著降低，表明Usp 14可以作为蛋白酶体的抑制剂起作用。我们的工作假设是，Usp 14的功能是编辑泛素侧链的蛋白质之前，他们的承诺，蛋白酶体降解，导致从蛋白酶体释放的底物。该建议的重点是确定Usp 14的泛素水解酶活性的丧失是否可以降低在亨廷顿病、额颞叶痴呆和帕金森病的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为患有慢性神经系统疾病的患者带来强大的新治疗选择。

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.