Increased SORBS3 expression in brain ageing contributes to autophagic decline via YAP1-WWTR1/TAZ signaling

Impaired autophagosome formation and reduced flux through the macroautophagy/autophagy pathway occurs outside the brain as part of normal aging in various species. We recently identified autophagic decline in mouse brain tissue dependent on aging. This sits alongside significantly increased expression of the Sorbs3/SORBS3/vinexin (sorbin and SH3 domain containing 3) gene in older mouse and human brains. We found that SORBS3 negatively regulates autophagy in several cell lines, including mouse primary neurons. SORBS3 depletion increases F-actin structures, which compete with YAP1-WWTR1/TAZ to bind AMOT (angiomotin) proteins in the cytosol. Unbound YAP1-WWTR1/TAZ is free to move into the nucleus and upregulate YAP1-WWTR1/TAZ target gene expression. This upregulates autophagosome formation, in part through increased expression of myosin- and actin-related genes. Moreover, we have shown these YAP1-WWTR1/TAZ target genes are downregulated in older mouse and human brains. Taken together, our findings suggest that increased SORBS3 expression contributes to autophagic decline in normal brain aging across species.

Automated summary

Impaired autophagosome formation and reduced flux through the macroautophagy/autophagy pathway occur outside the brain as part of normal aging. Our study found that SORBS3 gene expression is significantly increased in the brains of older mice and humans. SORBS3 negatively regulates autophagy in several cell lines and its depletion leads to increased autophagosome formation. The upregulation of YAP1-WWTR1/TAZ target genes, including myosin- and actin-related genes, contributes to this process. Moreover, we observed downregulation of these target genes in older mouse and human brains. These findings suggest that increased SORBS3 expression contributes to autophagic decline in normal brain aging.