Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Neurosci. 2011 Oct 12;31(41):14508-20. doi: 10.1523/JNEUROSCI.1560-11.2011.
Increased intracellular levels of α-synuclein are implicated in Parkinson's disease and related disorders and may be caused by alterations in the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal pathway (ALP). A critical question remains how α-synuclein is degraded by neurons in vivo. To address this, our study uses α-synuclein transgenic mice, expressing human α-synuclein or α-synuclein-eGFP under the (h)PDGF-β promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for α-synuclein under normal conditions in vivo while with increased α-synuclein burden the ALP is recruited. Moreover, we report alterations of the UPS in α-synuclein transgenic mice and age dependence to the role of the UPS in α-synuclein degradation. In addition, we provide evidence that the UPS and ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and α-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways.
α-突触核蛋白在帕金森病和相关疾病中的含量增加，这可能是由于泛素蛋白酶体系统 (UPS) 或自噬溶酶体途径 (ALP) 的改变所致。一个关键的问题仍然是α-突触核蛋白如何在体内被神经元降解。为了解决这个问题，我们的研究使用了α-突触核蛋白转基因小鼠，这些小鼠在 (h)PDGF-β 启动子的控制下表达人类α-突触核蛋白或α-突触核蛋白-eGFP，同时结合体内药理学和多光子成像策略，系统地测试活体小鼠大脑中的降解途径。我们证明，在正常情况下 UPS 是体内α-突触核蛋白的主要降解途径，而随着α-突触核蛋白负担的增加，ALP 被招募。此外，我们还报告了α-突触核蛋白转基因小鼠中 UPS 的改变以及 UPS 在α-突触核蛋白降解中的作用随年龄的变化。此外，我们提供了证据表明 UPS 和 ALP 可能具有功能连接，以至于一个的损伤可以上调另一个。这些结果为 UPS、ALP 和α-突触核蛋白病理学之间提供了新的联系，并可能对未来针对降解途径的治疗具有重要意义。
