Lanore Aymeric, Tesson Christelle, Basset Aymeric, Lejeune François-Xavier, Cogan Guillaume, Mangone Graziella, Sambin Sara, Bertille Nathalie, Anheim Mathieu, Arnulf Isabelle, Ansquer Solène, Brandel Jean-Philippe, Brefel-Courbon Christine, Defebvre Luc, Drapier Sophie, Eusebsio Alexandre, Fabbri Margherita, Giordana Caroline, Hainque Elodie, Lehericy Stephane, Marques Ana, Moreau Caroline, Moro Elena, Ory Fabienne, Rolland Anne-Sophie, Thobois Stéphane, Vidailhet Marie, Devos David, Mariani Louise-Laure, Lesage Suzanne, Brice Alexis, Corvol Jean-Christophe
Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.
Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.
NPJ Parkinsons Dis. 2025 Aug 2;11(1):226. doi: 10.1038/s41531-025-01060-6.
Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson's disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, and analysed their associations with enzyme activity, Saposin C (SapC) interaction and PD progression in 639 patients with heterozygous GBA1 variants from five cohorts. Principal component analysis (PCA) identified two components: PC1, associated with reduced β-glucocerebosidase activity, the GD clinical severity classification, younger age at PD diagnosis, and faster cognitive and motor decline; and PC2, associated with surface-exposed, flexible regions involved in SapC interactions, younger age at PD diagnosis, and slightly with motor decline. These findings highlight that impaired SapC interactions, in addition to reduced activity, may contribute to PD severity in GBA1 variant carriers. This is relevant for therapeutic approaches aimed at stabilizing β-glucocerebosidase or enhancing its enzymatic activity in PD.
双等位基因致病性GBA1变异导致戈谢病（GD），而某些杂合错义变异会增加帕金森病（PD）的风险，尽管其潜在机制尚不清楚。在此，我们使用预测和结构评分对GBA1错义变异进行分类，并分析了它们与来自五个队列的639例携带杂合GBA1变异患者的酶活性、鞘脂激活蛋白C（SapC）相互作用以及PD进展的关联。主成分分析（PCA）确定了两个成分：PC1与β-葡萄糖脑苷脂酶活性降低、GD临床严重程度分类、PD诊断时较年轻的年龄以及更快的认知和运动衰退相关；PC2与参与SapC相互作用的表面暴露的柔性区域、PD诊断时较年轻的年龄以及与运动衰退略有相关。这些发现突出表明，除了活性降低外，SapC相互作用受损可能导致GBA1变异携带者的PD严重程度增加。这与旨在稳定β-葡萄糖脑苷脂酶或增强其在PD中的酶活性的治疗方法相关。
