Molecular Pathology, International Institute for Genetic Engineering and Biotechnology, Trieste, Italy.
Regional Coordinator Centre for Rare Diseases, Academic Hospital Santa Maria della Misericordia, Udine, Italy.
J Biotechnol. 2020 Jul 20;318:20-30. doi: 10.1016/j.jbiotec.2020.03.012. Epub 2020 May 6.
Niemann-Pick type C (NPC) is an autosomal recessive lysosomal storage disorder due to mutations in NPC1 (95 % cases) or NPC2 genes, encoding NPC1 and NPC2 proteins, respectively. Both NPC1 and NPC2 proteins are involved in transport of intracellular cholesterol and their alteration leads to the accumulation of unesterified cholesterol and other lipids within the lysosomes. The disease is characterized by visceral, neurological and psychiatric symptoms. However, the pathogenic mechanisms that lead to the fatal neurodegeneration are still unclear. To date, several mutations leading to the generation of aberrant splicing variants or mRNA degradation in NPC1 and NPC2 genes have been reported. In addition, different lines of experimental evidence have highlighted the possible role of RNA-binding proteins and RNA-metabolism, in the onset and progression of many neurodegenerative disorders, that could explain NPC neurological features and in general, the disease pathogenesis. In this review, we will provide an overview of the impact of mRNA processing and metabolism on NPC disease pathology.
尼曼-匹克 C 型（NPC）是一种常染色体隐性溶酶体贮积症，由 NPC1（95%的病例）或 NPC2 基因突变引起，分别编码 NPC1 和 NPC2 蛋白。NPC1 和 NPC2 蛋白均参与细胞内胆固醇的转运，其改变导致未酯化胆固醇和其他脂质在内溶酶体中的积累。该疾病的特征为内脏、神经和精神症状。然而，导致致命神经退行性变的发病机制仍不清楚。迄今为止，已报道 NPC1 和 NPC2 基因中导致异常剪接变异体或 mRNA 降解的几种突变。此外，不同的实验证据表明，RNA 结合蛋白和 RNA 代谢在许多神经退行性疾病的发病和进展中可能发挥作用，这可以解释 NPC 的神经特征以及一般来说，疾病的发病机制。在这篇综述中，我们将概述 mRNA 处理和代谢对 NPC 疾病病理学的影响。
