Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
School of Life Sciences, Arizona State University, Tempe, AZ, USA.
Neurochem Res. 2020 Jun;45(6):1306-1327. doi: 10.1007/s11064-020-02989-1. Epub 2020 Feb 21.
The widespread nature of nucleocytoplasmic trafficking defects and protein accumulation suggests distinct yet overlapping mechanisms in a variety of neurodegenerative diseases. Detailed understanding of the cellular pathways involved in nucleocytoplasmic transport and its dysregulation are essential for elucidating neurodegenerative pathogenesis and pinpointing potential areas for therapeutic intervention. The transport of cargos from the nucleus to the cytoplasm is generally regulated by the structure and function of the nuclear pore as well as the karyopherin α/β, importin, exportin, and mRNA export mechanisms. The disruption of these crucial transport mechanisms has been extensively described in the context of neurodegenerative diseases. One common theme in neurodegeneration is the cytoplasmic aggregation of proteins, including nuclear RNA binding proteins, repeat expansion associated gene products, and tau. These cytoplasmic aggregations are partly a consequence of failed nucleocytoplasmic transport machinery, but can also further disrupt transport, creating cyclical feed-forward mechanisms that exacerbate neurodegeneration. Here we describe the canonical mechanisms that regulate nucleocytoplasmic trafficking as well as how these mechanisms falter in neurodegenerative diseases.
核质转运缺陷和蛋白质积累的广泛存在表明，在各种神经退行性疾病中存在不同但重叠的机制。详细了解参与核质转运及其失调的细胞途径对于阐明神经退行性发病机制和确定潜在的治疗干预领域至关重要。货物从细胞核到细胞质的运输通常受核孔的结构和功能以及核蛋白α/β、导入蛋白、输出蛋白和 mRNA 输出机制的调节。这些关键运输机制的破坏在神经退行性疾病的背景下已经得到了广泛的描述。神经退行性变的一个共同主题是蛋白质在细胞质中的聚集，包括核 RNA 结合蛋白、重复扩展相关基因产物和 tau。这些细胞质聚集部分是核质转运机制失败的结果，但也可以进一步破坏运输，形成恶性循环的反馈机制，加剧神经退行性变。在这里，我们描述了调节核质转运的典型机制，以及这些机制在神经退行性疾病中是如何失灵的。
