Shammas Hadeel, Kloster Fog Cathrine, Klein Pontus, Koustrup Anja, Pedersen Marianne Terndrup, Bie Anne Sigaard, Mickle Travis, Petersen Nikolaj Havnsøe Torp, Kirkegaard Jensen Thomas, Guenther Sven
Zevra Therapeutics, Celebration, FL, USA.
Orphazyme A/S, Copenhagen, Denmark.
Mol Genet Metab. 2025 May;145(1):109103. doi: 10.1016/j.ymgme.2025.109103. Epub 2025 Apr 2.
Niemann-Pick disease type C (NPC) is an ultra-rare, fatal neurodegenerative disease. It is characterized by lysosomal dysfunction with cytotoxic accumulation of unesterified cholesterol and glycosphingolipids in lysosomes, which causes neurodegeneration and peripheral organ dysfunction. Arimoclomol, an orally available small molecule, is the first FDA-approved treatment for NPC when used in combination with miglustat. Here, we present the results of a series of in vitro studies performed to explore the pathways by which arimoclomol targets the fundamentals of NPC etiology. While the precise cellular interactions of arimoclomol remain unclear, the increased translocation of the transcription factors EB and E3 (TFEB and TFE3) from the cytosol to the nucleus is a key initial step for triggering a cascade of downstream events that can rescue cellular functions. Activation of TFEB and TFE3 raises the expression rates of coordinated lysosomal expression and regulation (CLEAR) genes including NPC1 that are essential for the regulation of lysosomal function. The subsequent upregulation of CLEAR network proteins combined with increased unfolded protein response activation was shown to enlarge the pool of matured NPC1 capable of reaching the lysosome to reduce cholesterol accumulation. By also amplifying expression of CLEAR genes associated with autophagy, arimoclomol has the potential to act on different pathways and improve cell viability independent of NPC1 protein levels and functionality. In summary, the findings presented illustrate how arimoclomol improves lysosomal function and potentially autophagy flux to decrease lipid burden in NPC patient fibroblasts.
尼曼-匹克C型病（NPC）是一种极为罕见的致命性神经退行性疾病。其特征为溶酶体功能障碍，未酯化胆固醇和糖鞘脂在溶酶体中发生细胞毒性蓄积，进而导致神经退行性变和外周器官功能障碍。阿利克仑莫，一种口服可用的小分子药物，是首个经美国食品药品监督管理局（FDA）批准与米格鲁司他联合使用治疗NPC的药物。在此，我们展示了一系列体外研究的结果，这些研究旨在探索阿利克仑莫针对NPC病因学基础的作用途径。虽然阿利克仑莫确切的细胞相互作用尚不清楚，但转录因子EB和E3（TFEB和TFE3）从胞质溶胶向细胞核的转位增加是触发一系列可挽救细胞功能的下游事件的关键初始步骤。TFEB和TFE3的激活提高了包括NPC1在内的溶酶体协同表达与调控（CLEAR）基因的表达率，这些基因对于溶酶体功能的调节至关重要。随后CLEAR网络蛋白的上调以及未折叠蛋白反应激活的增加显示，可扩大能够到达溶酶体的成熟NPC1池，以减少胆固醇蓄积。通过放大与自噬相关的CLEAR基因的表达，阿利克仑莫有可能作用于不同途径并提高细胞活力，而与NPC1蛋白水平和功能无关。总之，本文呈现的研究结果阐明了阿利克仑莫如何改善溶酶体功能以及潜在的自噬通量，以减轻NPC患者成纤维细胞中的脂质负担。
