circPDE4B downregulation triggers GEMIN5‑dependent translational stress response and autophagy to reduce MAPT pathology

Abstract

Introduction: Circular RNAs (circRNAs) are emerging as key regulators of gene expression, synaptic plasticity, and neuronal function in Alzheimer's disease (AD). Here, we characterize the biological actions of circPDE4B, a highly expressed circRNA markedly reduced in AD.

Methods: circPDE4B knockdown in neuronal progenitor cells was combined with RNA sequencing to identify regulated pathways. circPDE4B affinity purification identified major protein and micro RNA (miRNA) interactors. Assays of translation and autophagy integrated circPDE4B actions.

Results: We found that circPDE4B knockdown inhibited translation through a mechanism mediated by its major interacting protein, gem-associated protein 5. circPDE4B knockdown also decreased mechanistic target of rapamycin and correspondingly enhanced autophagic flux. Consistent with these actions, circPDE4B knockdown strongly attenuated microtubule-associated protein tau pathology in a 3D human assembloid model of tauopathy.

Discussion: Collectively, our findings identify circPDE4B as a regulator of neuronal homeostasis that integrates translation, autophagy, and miRNA pathways, highlighting a potentially important role in the pathophysiology of AD.

Keywords: Alzheimer's disease; autophagy; circPDE4b; circular RNA; gem‐associated protein 5; microtubule‐associated protein tau pathology; neuronal homeostasis; translational regulation; translational stress response.