Department of Enzymology and Cellular Function, Institute of Child Health, Athens, Greece.
Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
PLoS One. 2023 Feb 3;18(2):e0277602. doi: 10.1371/journal.pone.0277602. eCollection 2023.
It is well established that patients with Gaucher disease, as well as carriers of the disease have an increased risk for developing Parkinson's disease. A plethora of evidence suggests that disturbed α-Synuclein homeostasis is the link between Gaucher disease and Parkinson's disease. The pathogenic mechanism linking these entities is still a topic of debate and both gain- and loss-of-function theories have been put forward, which however are not mutually exclusive. In the present study we expanded our previous studies to include not only Gaucher disease patients but also Gaucher disease carriers and Gaucher disease patients following Enzyme Replacement Therapy. In these groups we investigated α-Synuclein in red blood cell membranes in association with lipid abnormalities described in Gaucher disease. These included glucosylceramide and its species, glucosylsphingosine, glucosylcholesterol and plasmalogens. Increased oligomerization of α-Synuclein in red blood cell membranes was observed not only in Gaucher disease patients but also in carriers of the disease. There were no qualitative differences in the lipids identified in the groups studied. However, significant quantitative differences compared to controls were observed in Gaucher disease patients but not in Gaucher disease carriers. Enzyme Replacement Therapy reversed the biochemical defects and normalized α-Synuclein homeostasis, providing for the first time evidence in human subjects that such homeostatic dysregulation is reversible. Further studies investigating α-Synuclein status during the differentiation of erythroid progenitors could provide new data on the pathogenic mechanism of α-Synuclein oligomerization in this system.
已有充分的证据表明，戈谢病患者以及该病的携带者发生帕金森病的风险增加。大量证据表明，α-突触核蛋白的动态平衡紊乱是戈谢病与帕金森病之间的联系。将这些实体联系起来的致病机制仍然是一个争论的话题，提出了功能获得和功能丧失两种理论，但它们并不相互排斥。在本研究中，我们扩展了之前的研究，不仅包括戈谢病患者，还包括戈谢病携带者以及接受酶替代治疗的戈谢病患者。在这些组中，我们研究了红细胞膜中的α-突触核蛋白与戈谢病中描述的脂质异常相关联。这些异常包括葡萄糖神经酰胺及其物种、葡萄糖鞘氨醇、葡萄糖胆固醇和血浆类脂。不仅在戈谢病患者中，而且在该病的携带者中，也观察到红细胞膜中α-突触核蛋白的寡聚化增加。在研究的组中未观察到脂质的定性差异。然而，与对照组相比，戈谢病患者中观察到显著的定量差异，但在戈谢病携带者中未观察到。酶替代治疗逆转了生化缺陷并使α-突触核蛋白的动态平衡正常化，首次为人类提供了证据，证明这种动态平衡失调是可以逆转的。进一步研究红细胞祖细胞分化过程中的α-突触核蛋白状态，可以为该系统中α-突触核蛋白寡聚化的致病机制提供新的数据。
