FUS phosphorylation and its significance in ALS

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. Several ALS genes have been identified, including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma (FUS). FUS is a ubiquitously expressed RNA-binding protein that is predominantly localized in the nucleus. FUS plays a role in a variety of processes including transcriptional regulation and mRNA splicing. However, little is known regarding how FUS function is regulated. The hypothesis to be tested is that phosphorylation of FUS by CK2 plays a critical role in regulating FUS function and that inhibition of FUS phosphorylation can mitigate its toxicity. We recently found that FUS is phosphorylated by casein kinase 2 (CK2) and identified several potential phosphorylation sites. Co-expression of CK2 exacerbated the locomotive impairment of FUS transgenic flies whereas the CK2 phosphorylation-deficient mutant of FUS reduced toxicity in flies. The results suggest that phosphorylation of FUS by CK2 can directly modulate FUS toxicity. We will determine the effect of inhibiting FUS phosphorylation on FUS toxicity in vivo using fly models. We will determine the exact CK2 phosphorylation site(s) using mass spectrometry and investigate the significance of individual phosphorylation site. This project will not only yield novel mechanistic insights on regulation of FUS function by CK2 phosphorylation, but also determine whether CK2 inhibition can be a new therapeutic avenue.