Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors

SIMPLE SUMMARY: Aberrant protein phase transitions and aggregation trigger various neurodegenerative diseases, including ALS, FTD, Alzheimer’s disease, and Huntington’s disease. Dynamic exchange of proteins and RNA between the nucleus and cytoplasm is essential for cellular functioning, which is greatly affected by the mislocalization, phase separation, and aggregation of different RNA-binding proteins (RBPs), such as FUS, TDP-43, and hnRNPA1/A2 in their respective neurodegenerative diseases. Disease-linked abnormal accumulation of these RBPs impairs the nucleocytoplasmic transport (NCT) by disrupting the nuclear envelope architecture and mislocalizing essential NCT factors, such as nucleoporins, importins, exportins, and the Ran protein and its regulatory components. Nuclear import receptors (NIRs) have the potential to restore abnormal mislocalization of RBPs by regulating the import/export pathway. NIRs can also potentially prevent or reverse the phase separation and fibrillization of RBPs. Overall, this review focuses on the role of nuclear import receptors in regulating phase transitions in neurodegenerative diseases. ABSTRACT: RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major event observed in ageing and in neurodegenerative disorders. Nuclear import receptors (NIRs) regulate the nucleocytoplasmic transport of different RBPs bearing a nuclear localization signal by restoring their nuclear localization. NIRs can also specifically dissolve or prevent the aggregation and liquid–liquid phase separation of wild-type or disease-linked mutant RBPs, due to their chaperoning activity. This review focuses on the LLPS of intrinsically disordered proteins and the role of NIRs in regulating LLPS in neurodegeneration. This review also discusses the implication of NIRs as therapeutic agents in neurogenerative diseases.