The role of the Leucine-Rich (LeuR) domain of Rho Guanine Nucleotide Exchange Factor (RGNEF) in the regulation of amyotrophic lateral sclerosis (ALS) associated protein TAR DNA-binding protein of 43 KDa (TDP-43)
Abstract
The presence of neuronal cytoplasmic inclusions (NCIs) composed of RNA-binding proteins (RBPs) and neurofilaments is considered to be ALS’s neuropathological hallmark. RGNEF has been previously shown to interact with TDP-43 and to have a regulatory effect on the expression levels of NEFL mRNA and NFL protein in vitro. Here, I examined the mechanism of the RGNEF N-terminus, leucine-rich domain (LeuR) domain’s interaction with TDP-43. I observed that the minimal domain required is 110 amino acids (LeuR110), that the Ankyrin domain adjacent to LeuR110 does not participate, and that LeuR110 forms of a high molecular weight complex with TDP-43 in vitro consistent with the co-aggregation of LeuR242 and TDP-43 in double transgenic drosophila melanogaster. I also observed that RGNEF interacts directly with and destabilizes the TARDBP mRNA 3’UTR. These findings support that RGNEF interacts with TDP-43 through the formation of a high molecular weight complex and the down-regulation of its expression.