Dataset Information

Alzheimer’s Disease-Associated circPDE4B Triggers Translation Stress Pathways

ABSTRACT: In the intricate landscape of Alzheimer’s disease (AD) pathology, circular RNAs(circRNA) are emerging as influential players, orchestrating crucial aspects of gene expression, synaptic plasticity, and neuronal function. In this study, we characterize the biological role of circPDE4B, a highly abundant circRNA that is markedly downregulated in AD across brain regions. Unlike most circRNAs, circPDE4B is expressed at substantially higher levels than its linear PDE4B transcript, suggesting a distinctive regulatory significance. Functional analyses in neuronal precursor cells revealed that circPDE4B reduction triggers a translational stress response, indicating its critical role in maintaining protein synthesis homeostasis. Immunoprecipitation identified several RNA-binding proteins associated with circPDE4B, among which the translation factor Gemin5 emerged as a key mediator of its effects on translation. Loss of circPDE4B also reduced mTOR levels and subsequently enhanced autophagic flux. Notably, circPDE4B downregulation was sufficient to mitigate tau pathology in a 3D assembloid model of tauopathy. We also identified a subset of AD-associated miRNAs interacting with circPDE4B, implicating additional layers of post-transcriptional regulation. Collectively, these findings define circPDE4B as a multifunctional regulator of neuronal homeostasis that integrates translational control, autophagic activity, and miRNA-mediated pathways, illuminating its potential involvement in the stress response and pathophysiology of AD

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neural Progenitor Cell

SUBMITTER: Sophie van der Spek