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，但加速蛋白酶体活性用于医学目的的想法代表了有害蛋白质积聚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，如帕金森病、阿尔茨海默病、亨廷顿病、额颞叶痴呆和脊髓小脑共济失调，其特征是泛素化蛋白聚集物的存在和蛋白酶体功能的降低。因此，虽然这些突变蛋白可以作为蛋白酶体降解的靶点，但它们不能被泛素蛋白酶体系统有效地消除。我们最近确定遗传或药理学抑制Usp14的泛素水解酶活性足以加速蛋白酶体的蛋白质降解。抑制Usp14的泛素水解酶活性后，tau、TDP-43和ataxin-3等蛋白水平显著降低，表明Usp14可以作为蛋白酶体的抑制剂。我们的工作假设是Usp14的功能是在蛋白酶体降解之前编辑蛋白质的泛素侧链，从而导致蛋白酶体释放底物。这项提议的重点是确定Usp14的泛素水解酶活性的丧失是否可以降低亨廷顿病、额颞叶痴呆和帕金森病动物模型中产生的聚集易感性蛋白的水平。这种增强蛋白酶体清除聚集易感性蛋白功能的新方法可能为慢性神经系统疾病患者提供一种强有力的新治疗选择。

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.