α-synuclein is degraded by both autophagy and the proteasome
α-synuclein is degraded by both autophagy and the proteasome
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DOI：
10.1074/jbc.m300227200
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发表时间：
2003-07-04
影响因子：
4.8
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
--
作者：
Webb, JL;Ravikumar, B;Rubinsztein, DC
帕金森病(PD)的特征是黑质多巴胺能神经元的丢失和神经元内聚集(路易小体)的形成。α-突触核蛋白是路易体的主要蛋白质，α-突触核蛋白的罕见突变导致早发性帕金森病。因此，α-突触核蛋白参与了帕金森病的发病机制。在这里，我们使用一个稳定的可诱导的PC12细胞模型来研究α-突触核蛋白的降解途径，在该模型中，外源人野生型A30P或A53Tα-突触核蛋白的表达可以被开启和关闭。我们使用了一组自噬和蛋白酶体功能的抑制剂/刺激剂，并跟踪了这些细胞中α-突触核蛋白的降解。我们发现，α-突触核蛋白不仅被蛋白酶体降解，而且还被自噬降解。细胞器中具有自噬小泡超微结构特征的α-突触核蛋白的存在进一步支持了自噬的作用。由于雷帕霉素是一种自噬刺激剂，可以增加α-突触核蛋白的清除，因此值得考虑将其作为治疗帕金森氏病的潜在药物，因为它是为人类慢性使用而设计的。
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates ( Lewy bodies) in neurons. alpha-Synuclein is the major protein in Lewy bodies and rare mutations in alpha-synuclein cause early-onset PD. Consequently, alpha-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of alpha-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T alpha-synuclein can be switched on and off. We have used a panel of inhibitors/stimulators of autophagy and proteasome function and followed alpha-synuclein degradation in these cells. We found that not only is alpha-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of alpha-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of alpha-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.