Ubiquitin-proteasome pathway components as therapeutic targets for CNS maladies.
Ubiquitin-proteasome pathway components as therapeutic targets for CNS maladies.
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DOI：
10.2174/138161205774580651
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发表时间：
2005-10
影响因子：
3.1
通讯作者：
Sudarshan C. Upadhya;A. Hegde
中科院分区：
文献类型：
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作者：
Sudarshan C. Upadhya;A. Hegde
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通常与几种神经退行性疾病相关。泛素化的蛋白质聚集体被认为是由泛素-蛋白酶体途径的功能障碍或过载或由蛋白质底物的结构变化引起的，所述结构变化阻止了它们被泛素-蛋白酶体途径识别和降解。受损的蛋白水解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的特异性由特异性泛素连接酶（E3）决定，因此鉴定特异性E3及其变构调节剂可能为治疗几种CNS疾病提供有效的治疗靶点。另一个尚未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，但没有有效的药物可以刺激蛋白酶体。由于异常蛋白质聚集是不同神经退行性疾病的共同特征，因此增强蛋白酶体活性可能是去除在脑中积累的聚集物的有效方法。在这篇综述中，我们讨论了泛素-蛋白酶体通路的组成部分如何成为治疗中枢神经系统疾病和障碍的潜在靶点。
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.