Professor Zhou Rongjia's team at the College of Life Sciences, Wuhan University, in collaboration with Professor Cheng Hanhua's group, has published a groundbreaking study in the journal Autophagy.

The research, titled “Inflammatory signaling attenuates spliceosome function and cognitive ability”, discovers a novel molecular mechanism by which inflammatory signaling impairs spliceosome function, leading to cognitive decline through the FGF2-hnRNPA1-ATG16L1 signaling axis.

Using mouse models of acute kidney injury (AKI) and COVID-19-induced inflammation, the team found that inflammation activates FGF2, which in turn causes the splicing factor hnRNPA1 to move from the nucleus to the cytoplasm, where it is degraded via the autophagy pathway.

This reduction in nuclear hnRNPA1 levels results in abnormal exon skipping in the precursor mRNA of the autophagy-related gene ATG16L1, reducing the expression of the ATG16L1α isoform and impairing autophagy function.

These molecular alterations hinder the clearance of amyloid precursor protein (APP) oligomers in the hippocampus, leading to their pathological accumulation and subsequent cognitive dysfunction.

The study also demonstrated that the FGFR inhibitor erdafitinib can partially restore autophagy function and improve cognitive performance. In mice lacking the fgf2 gene, hnRNPA1 remained in the nucleus, maintaining normal ATG16L1 splicing and autophagy function, even under AKI-induced inflammation, thereby preventing significant cognitive impairment.

This research provides crucial insights into how inflammatory signaling disrupts cellular homeostasis via the FGF2-hnRNPA1-ATG16L1 axis, resulting in spliceosome dysfunction and cognitive decline.

It also identifies new potential targets for therapeutic interventions to mitigate cognitive dysfunction and offers innovative strategies for preventing cognitive deterioration.