Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Rev Neurol. 2022 Jun;18(6):348-362. doi: 10.1038/s41582-022-00653-6. Epub 2022 Apr 29.
The genetic underpinnings and end-stage pathological hallmarks of neurodegenerative diseases are increasingly well defined, but the cellular pathophysiology of disease initiation and propagation remains poorly understood, especially in sporadic forms of these diseases. Altered nucleocytoplasmic transport is emerging as a prominent pathomechanism of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and Huntington disease. The nuclear pore complex (NPC) and interactions between its individual nucleoporin components and nuclear transport receptors regulate nucleocytoplasmic transport, as well as genome organization and gene expression. Specific nucleoporin abnormalities have been identified in sporadic and familial forms of neurodegenerative disease, and these alterations are thought to contribute to disrupted nucleocytoplasmic transport. The specific nucleoporins and nucleocytoplasmic transport proteins that have been linked to different neurodegenerative diseases are partially distinct, suggesting that NPC injury contributes to the cellular specificity of neurodegenerative disease and could be an early initiator of the pathophysiological cascades that underlie neurodegenerative disease. This concept is consistent with the fact that rare genetic mutations in some nucleoporins cause cell-type-specific neurological disease. In this Review, we discuss nucleoporin and NPC disruptions and consider their impact on cellular function and the pathophysiology of neurodegenerative disease.
神经退行性疾病的遗传基础和终末期病理特征越来越明确，但疾病起始和传播的细胞病理生理学仍知之甚少，尤其是在这些疾病的散发性形式中。核质转运的改变正在成为多种神经退行性疾病的突出病理机制，包括肌萎缩侧索硬化症、阿尔茨海默病、额颞叶痴呆和亨廷顿病。核孔复合体 (NPC) 及其各个核孔蛋白成分与核转运受体之间的相互作用调节核质转运以及基因组组织和基因表达。在神经退行性疾病的散发性和家族性形式中已经确定了特定的核孔蛋白异常，这些改变被认为导致核质转运中断。与不同神经退行性疾病相关的特定核孔蛋白和核质转运蛋白部分不同，这表明 NPC 损伤有助于神经退行性疾病的细胞特异性，并且可能是神经退行性疾病潜在病理生理级联反应的早期启动因素。这一概念与某些核孔蛋白中的罕见基因突变导致细胞类型特异性神经疾病的事实一致。在这篇综述中，我们讨论了核孔蛋白和 NPC 的破坏，并考虑了它们对细胞功能和神经退行性疾病病理生理学的影响。
