Figure 2.

Functional loss of FUS in the nucleus and the cytoplasm can cause neuronal dysfunction and degeneration. In the nucleus, FUS regulates alternative splicing and transcription. For instance, exon 10 skipping of MAPT, which is regulated by FUS in complex with SFPQ, generates two isoforms of Tau protein, 3R-Tau and 4R-Tau. FUS also regulates transcription of a number of genes including Ntng1, Braf1, and Fus itself. On the other hand, cytoplasmic FUS stabilizes mRNAs involved in the dendritic spine, such as GluA1 and SynGAP. Taken together, the functional impairments caused by FUS deficiency can affect neuronal function and morphology and subsequently lead to aberrant behaviors and neurodegeneration. In addition, FUS has also been implicated in the axon transport machinery, which is impaired by disease-associated mutations in FUS.