The Hitchhiker’s Guide to Nucleocytoplasmic Trafficking in Neurodegeneration

• Published in: Neurochemical research Vol. 45; no. 6; pp. 1306 - 1327
• Main Authors: Moore, Stephen, Rabichow, Benjamin E., Sattler, Rita
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2020; Springer Nature B.V
• Subjects: Active Transport, Cell Nucleus - physiology; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cytoplasm; Humans; mRNA; Neurochemistry; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurology; Neurosciences; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Pathogenesis; Protein transport; Protein Transport - physiology; Proteins; Review Article; RNA-binding protein; Structure-function relationships; Tau protein; Proteinopathy; ALS/FTD; Huntington’s disease; Alzheimer’s disease; FUS; TDP-43
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-020-02989-1

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.