Centre National de la Recherche Scientifique, Université de Strasbourg, Institute of Cellular and Integrative Neurosciences, Strasbourg, France.
Prog Lipid Res. 2023 Apr;90:101225. doi: 10.1016/j.plipres.2023.101225. Epub 2023 Mar 31.
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
细胞内脂质平衡紊乱会引发人类疾病。阐明其潜在机制并开发有效的治疗方法是生物医学研究面临的巨大挑战。两个罕见的常染色体隐性、最终致命的溶酶体疾病就是典型的例子，它们以发现它们的两位医生的名字命名，即“尼曼-匹克”，以表彰他们的开创性观察。酸性鞘磷脂酶缺乏症（ASMD）和尼曼-匹克 C 型疾病（NPCD）是由鞘磷脂磷酸二酯酶 1（SMPD1）和 NPC 细胞内胆固醇转运蛋白 1（NPC1）或 NPC 细胞内胆固醇转运蛋白 2（NPC2）基因的特定变体引起的，这些变体分别破坏了两种关键膜成分——鞘磷脂和胆固醇的平衡。这些疾病的严重形式会导致内脏和神经症状，并导致过早死亡。这篇综述追溯了尼曼-匹克疾病的曲折发现过程，强调了与遗传罪魁祸首和细胞机制相关的重要进展，并揭示了改善诊断和探索新治疗方法的努力。
