Abstract 2706 Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS

The formation of cytoplasmic protein aggregates is a hallmark in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).A nuclear import receptor, karyopherin b2 (Kapb2), mitigates mislocalization and aggregation of RNA-binding proteins (RBPs), such as fused in sarcoma (FUS).Kapb2 binds FUS through the nuclear localization signal (NLS) and acts as a chaperone.However, disease-causing mutations in FUS NLS compromise Kapb2 binding and activity.We engineered a chimeric protein, FUS-IBB that is potentiated to bind another nuclear import receptor, Importin b1 (Impb).We used in vitro aggregation assay and immunofluorescence imaging to characterize FUS-IBB properties and found that Impb can mitigate FUS-IBB aggregation.Moreover, the expression of FUS-IBB in cultured cells reduced the level of endogenous FUS, presumably through its negative feedback mechanism.The FUS-IBB can potentially replace the aggregation-prone endogenous FUS to restore neuronal function, which can be a therapeutic strategy.