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，但疾病发生和传播的细胞病理生理学仍然知之甚少，特别是在这些疾病的散发形式中。核细胞质运输的改变正在成为多种神经退行性疾病的重要病理机制，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和核转运受体之间的相互作用调节核细胞质转运以及基因组组织和基因表达。在散发性和家族性神经退行性疾病中已发现特定的核孔蛋白异常，这些改变被认为导致核细胞质运输中断。与不同神经退行性疾病相关的特定核孔蛋白和核细胞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基础病理生理级联的早期启动者。这一概念与一些核孔蛋白的罕见基因突变导致细胞类型特异性神经系统疾病的事实是一致的。在这篇综述中，我们讨论了核孔蛋白和 NPC 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。