Ducatez Franklin, Berger Marc G, Pilon Carine, Plichet Thomas, Lesueur Céline, Berger Juliette, Belmatoug Nadia, Marret Stéphane, Bekri Soumeya, Tebani Abdellah
Department of Metabolic Biochemistry, Referral Center for Lysosomal Diseases, Normandie Univ, UNIROUEN, CHU Rouen, INSERM U1245, Filière G2M, 76000, Rouen, France.
Department of Neonatal Pediatrics, Intensive Care and Neuropediatrics, Referral Center for Lysosomal Diseases, Normandie Univ, UNIROUEN, CHU Rouen, INSERM U1245, Filière G2M, 76000, Rouen, France.
J Mol Med (Berl). 2025 Feb;103(2):187-203. doi: 10.1007/s00109-024-02512-x. Epub 2024 Dec 30.
Gaucher disease (GD), an autosomal recessive lysosomal disorder, primarily affects the lysosomal enzyme β-glucocerebrosidase (GCase), leading to glucosylceramide accumulation in lysosomes. GD presents a wide spectrum of clinical manifestations. This study deploys immune-based proteomics and mass spectrometry-based metabolomics technologies to comprehensively investigate the biochemical landscape in 43 deeply phenotyped type 1 GD patients compared to 59 controls. Conventional and systems biology approaches have been used to analyze the data. The results show promising biological imprints. Elevated phosphatidylcholines in GD patients suggest altered lipid metabolism, potentially due to their increased synthesis. This points to endoplasmic reticulum stress and impaired lipid trafficking, commonly seen in lysosomal diseases. GD patients exhibit an inflammatory profile with elevated cytokines and autoimmune-like inflammation, even in treated patients, highlighting the complexity of GD-related immune imbalances. Mitochondrial dysfunction clues are found through increased oxidative stress markers and altered acylcarnitine profiles in GD patients, suggesting mitochondrial membrane dysfunction affecting carnitine-carrying capacity. Furthermore, platelet count, splenectomy, treatment, and clinical traits were associated with specific omics features, providing insights into GD's clinical heterogeneity and potential diagnostic markers. Autophagy inhibition appears pivotal in GD, driving lipid synthesis, impaired mitochondrial function, and inflammation through chronic activation of mTORC1. Despite limitations like focusing on type 1 GD and using targeted omics approaches, this study provides valuable insights into GD metabolic and immune dysregulation. It lays the basis for future comprehensive investigations into GD manifestations with broader scope and molecular coverage. KEY MESSAGES: The study sheds light on metabolic and immune dysregulation in Gaucher disease. Gaucher disease patients showed elevated phosphatidylcholines, disrupted lipid metabolism, and inflammation profiles. Signs of mitochondrial dysfunction are evident in Gaucher disease patients, with autophagy inhibition significantly affecting lipid synthesis, mitochondrial function, and inflammation via chronic activation of mTORC1.
戈谢病（GD）是一种常染色体隐性溶酶体疾病，主要影响溶酶体酶β-葡萄糖脑苷脂酶（GCase），导致溶酶体中葡糖神经酰胺蓄积。GD具有广泛的临床表现。本研究采用基于免疫的蛋白质组学和基于质谱的代谢组学技术，全面研究了43例深度表型分型的1型GD患者与59例对照的生化格局。采用传统和系统生物学方法分析数据。结果显示出有前景的生物学印记。GD患者中磷脂酰胆碱升高表明脂质代谢改变，可能是由于其合成增加。这指向内质网应激和脂质转运受损，这在溶酶体疾病中很常见。GD患者表现出炎症特征，细胞因子升高以及类似自身免疫的炎症，即使是接受治疗的患者也是如此，这突出了GD相关免疫失衡的复杂性。通过GD患者中氧化应激标志物增加和酰基肉碱谱改变发现线粒体功能障碍线索，表明线粒体膜功能障碍影响肉碱携带能力。此外，血小板计数、脾切除术、治疗和临床特征与特定的组学特征相关，为GD的临床异质性和潜在诊断标志物提供了见解。自噬抑制在GD中似乎至关重要，通过mTORC1的慢性激活驱动脂质合成、线粒体功能受损和炎症。尽管存在诸如专注于1型GD和使用靶向组学方法等局限性，但本研究为GD的代谢和免疫失调提供了有价值的见解。它为未来更广泛范围和分子覆盖的GD表现综合研究奠定了基础。关键信息：该研究揭示了戈谢病的代谢和免疫失调。戈谢病患者显示磷脂酰胆碱升高、脂质代谢紊乱和炎症特征。戈谢病患者中线粒体功能障碍的迹象明显，自噬抑制通过mTORC1的慢性激活显著影响脂质合成、线粒体功能和炎症。
