FMRP-PKA Activity Negative Feedback Regulates RNA Binding-Dependent Fibrillation in Brain Learning and Memory Circuitry.

ABSTRACT: Fragile X mental retardation protein (FMRP) promotes cyclic AMP (cAMP) signaling. Using an in vivo protein kinase A activity sensor (PKA-SPARK), we find that Drosophila FMRP (dFMRP) and human FMRP (hFMRP) enhance PKA activity in a central brain learning and memory center. Increasing neuronal PKA activity suppresses FMRP in Kenyon cells, demonstrating an FMRP-PKA negative feedback loop. A patient-derived R140Q FMRP point mutation mislocalizes PKA-SPARK activity, whereas deletion of the RNA-binding arginine-glycine-glycine (RGG) box (hFMRP-ΔRGG) produces fibrillar PKA-SPARK assemblies colocalizing with ribonucleoprotein (RNP) and aggregation (thioflavin T) markers, demonstrating fibrillar partitioning of cytosolic protein aggregates. hFMRP-ΔRGG reduces dFMRP levels, indicating RGG-independen

SUBMITTER: Sears JC 

PROVIDER: S-EPMC7590955 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature