Upadhya Sudarshan C, Hegde Ashok N
Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Curr Pharm Des. 2005;11(29):3807-28. doi: 10.2174/138161205774580651.
In the central nervous system (CNS), abnormal deposition of insoluble protein aggregates or inclusion bodies within nerve cells is commonly observed in association with several neurodegenerative diseases. The ubiquitinated protein aggregates are believed to result from malfunction or overload of the ubiquitin-proteasome pathway or from structural changes in the protein substrates which prevent their recognition and degradation by the ubiquitin-proteasome pathway. Impaired proteolysis might also contribute to the synaptic dysfunction seen early in neurodegenerative diseases because the ubiquitin-proteasome pathway is known to play a role in normal functioning of synapses. Because specificity of the ubiquitin proteasome mediated proteolysis is determined by specific ubiquitin ligases (E3s), identification of specific E3s and their allosteric modulators are likely to provide effective therapeutic targets for the treatment of several CNS disorders. Another unexplored area for the discovery of drug targets is the proteasome. Although many inhibitors of the proteasome are available, no effective drugs exist that can stimulate the proteasome. Since abnormal protein aggregation is a common feature of different neurodegenerative diseases, enhancement of proteasome activity might be an efficient way to remove the aggregates that accumulate in the brain. In this review, we discuss how the components of the ubiquitin-proteasome pathway could be potential targets for therapy of CNS diseases and disorders.
在中枢神经系统(CNS)中,神经细胞内不溶性蛋白质聚集体或包涵体的异常沉积在多种神经退行性疾病中较为常见。泛素化蛋白质聚集体被认为是泛素-蛋白酶体途径功能异常或过载,或者是蛋白质底物结构改变导致其无法被泛素-蛋白酶体途径识别和降解所致。蛋白水解受损也可能导致神经退行性疾病早期出现的突触功能障碍,因为已知泛素-蛋白酶体途径在突触的正常功能中发挥作用。由于泛素蛋白酶体介导的蛋白水解特异性由特定的泛素连接酶(E3)决定,鉴定特定的E3及其变构调节剂可能为治疗多种中枢神经系统疾病提供有效的治疗靶点。另一个未被探索的药物靶点发现领域是蛋白酶体。虽然有许多蛋白酶体抑制剂,但不存在能刺激蛋白酶体的有效药物。由于异常蛋白质聚集是不同神经退行性疾病的共同特征,增强蛋白酶体活性可能是清除大脑中积累的聚集体的有效方法。在本综述中,我们讨论了泛素-蛋白酶体途径的组成部分如何可能成为中枢神经系统疾病和障碍治疗的潜在靶点。