The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy
The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy
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DOI：
10.1096/fj.05-5126fje
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发表时间：
2006-01-01
期刊：
影响因子：
4.8
通讯作者：
Engelborghs, Y
中科院分区：
文献类型：
--
作者：
Gerard, M;Debyser, Z;Engelborghs, Y
α-突触核蛋白聚集(α-SYN)在帕金森病(PD)中起着关键作用。我们使用荧光相关光谱(FCS)研究了α-SYN的体外聚集，发现FK506结合蛋白(FKBPs)的加入明显加速了这一过程。这种作用在大肠杆菌SlyD FKBP和人FKBP12中都观察到，并被FKBP的特异性抑制剂FK506所抵消。在FKBP12存在下形成的α-SYN聚集体呈纤维状。FKBP的酶活性明显加快了α-SYN的折叠和随后的聚集。由于已知FK506和其他非免疫抑制的FKBP抑制剂在疾病模型中表现出神经再生和神经保护特性，观察到的对轮胺酶活性和α-SYN聚集的抑制可能解释了它们的作用模式。我们的结果为使用抑制FKBP家族特定成员的免疫亲和素配体治疗帕金森病开辟了前景。
Aggregation of alpha-synuclein (alpha-SYN) plays a key role in Parkinson's disease (PD). We have used fluorescence correlation spectroscopy (FCS) to study alpha-SYN aggregation in vitro and discovered that this process is clearly accelerated by addition of FK506 binding proteins (FKBPs). This effect was observed both with E. coli SlyD FKBP and with human FKBP12 and was counteracted by FK506, a specific inhibitor of FKBP. The alpha-SYN aggregates formed in the presence of FKBP12 showed fibrillar morphology. The rotamase activity of FKBP apparently accelerates the folding and subsequent aggregation of alpha-SYN. Since FK506 and other nonimmunosuppressive FKBP inhibitors are known to display neuroregenerative and neuroprotective properties in disease models, the observed inhibition of rotamase activity and alpha-SYN aggregation, may explain their mode of action. Our results open perspectives for the treatment of PD with immunophilin ligands that inhibit a specific member of the FKBP family.