Cooperative nuclear action of RNA-binding proteins PSF and G3BP2 to sustain neuronal cell viability is decreased in aging and dementia.

Abstract

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer's disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging- and AD-associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA-seq) analysis of human neuronal cells has shown that PSF is responsible for neuron-specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF-mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis demonstrated that the interaction of RBPs with the pre-mRNA of target genes enhanced post-transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non-AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development.