Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, and ‡Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
Biochemistry. 2013 Oct 15;52(41):7161-3. doi: 10.1021/bi401191v. Epub 2013 Oct 1.
Mutations in GBA1, the gene for glucocerebrosidase (GCase), are genetic risk factors for Parkinson disease (PD). α-Synuclein (α-Syn), a protein implicated in PD, interacts with GCase and efficiently inhibits enzyme activity. GCase deficiency causes the lysosomal storage disorder Gaucher disease (GD). We show that saposin C (Sap C), a protein vital for GCase activity in vivo, protects GCase against α-syn inhibition. Using nuclear magnetic resonance spectroscopy, site-specific fluorescence, and Förster energy transfer probes, Sap C was observed to displace α-syn from GCase in solution and on lipid vesicles. Our results suggest that Sap C might play a crucial role in GD-related PD.
GBA1 基因突变是帕金森病（PD）的遗传风险因素。α-突触核蛋白（α-Syn）是 PD 中的一种蛋白，与 GCase 相互作用并能有效抑制酶活性。GCase 缺乏会导致溶酶体贮积症——戈谢病（GD）。我们发现，对于 GCase 在体内的活性非常重要的脑苷脂激活蛋白 C（Sap C）能够保护 GCase 免受 α-Syn 的抑制。利用核磁共振波谱、荧光定位和Förster 能量转移探针，我们发现 Sap C 可以在溶液中和脂质体上置换与 GCase 结合的 α-Syn。我们的结果提示 Sap C 可能在 GD 相关 PD 中发挥关键作用。
