Department of Neurodegenerative Disease, University College London Institute of Neurology , London, United Kingdom .
Antioxid Redox Signal. 2014 Dec 10;21(17):2302-21. doi: 10.1089/ars.2013.5802. Epub 2014 Feb 27.
Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of a wide variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. The most significant risk factor for the development of these disorders is aging, which is associated with a progressive decline in UPS activity and the accumulation of oxidatively modified proteins. To date, no therapies have been developed that can specifically up-regulate this system.
In the neurodegenerative brain, dysfunction of the UPS has been associated with the deposition of ubiquitinated protein aggregates and widespread disruption of the proteostasis network. Recent research has identified further evidence of impairment in substrate ubiquitination and proteasomal degradation, which could contribute to the loss of cellular proteostasis in neurodegenerative disease. Novel strategies for activation of the UPS by genetic manipulation and treatment with synthetic compounds have also recently been identified.
Here, we discuss the specific roles of the UPS in the healthy central nervous system and establish how dysfunctional components can contribute to neurotoxicity in the context of disease.
Knowledge of the UPS components that are specifically or preferentially involved in neurodegenerative disease will be critical in the development of targeted therapies which aim at limiting the accumulation of misfolded proteins without gross disturbance of this major proteolytic pathway.
泛素-蛋白酶体系统 (UPS) 的损伤与多种神经退行性疾病的发病机制有关，包括阿尔茨海默病、帕金森病和亨廷顿病。这些疾病发展的最重要危险因素是衰老，这与 UPS 活性的逐渐下降和氧化修饰蛋白的积累有关。迄今为止，尚未开发出可以特异性上调该系统的疗法。
在神经退行性脑疾病中，UPS 的功能障碍与泛素化蛋白聚集体的沉积和广泛的蛋白质稳态网络破坏有关。最近的研究进一步证实了底物泛素化和蛋白酶体降解的损伤，这可能导致神经退行性疾病中细胞蛋白质稳态的丧失。通过遗传操作和合成化合物治疗激活 UPS 的新策略也最近被确定。
在这里，我们讨论了 UPS 在健康中枢神经系统中的特定作用，并确定了功能失调的成分如何在疾病背景下导致神经毒性。
了解特定或优先参与神经退行性疾病的 UPS 成分对于开发靶向治疗至关重要，这些治疗旨在限制错误折叠蛋白的积累，而不会对这一主要蛋白水解途径造成严重干扰。
