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

Cell Rep. 2020 Oct 13;33(2):108266. doi: 10.1016/j.celrep.2020.108266.


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-independent regulation. Short-term hFMRP-ΔRGG induction produces activated PKA-SPARK puncta, whereas long induction drives fibrillar assembly. Elevated temperature disassociates hFMRP-ΔRGG aggregates and blocks activated PKA-SPARK localization. These results suggest that FMRP regulates compartmentalized signaling via complex assembly, directing PKA activity localization, with FMRP RGG box RNA binding restricting separation via low-complexity interactions.

Keywords: Drosophila; FMRP; FXS; PKA; fragile X mental retardation protein; fragile X syndrome; mushroom body; protein kinase A.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Axons / metabolism
  • Biomarkers / metabolism
  • Brain / metabolism*
  • Cell Aggregation
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cytosol / metabolism
  • Drosophila melanogaster / metabolism
  • Feedback, Physiological*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Humans
  • Memory*
  • Mushroom Bodies / metabolism
  • Mutation / genetics
  • RNA / metabolism*
  • Ribonucleoproteins / metabolism


  • Biomarkers
  • Ribonucleoproteins
  • Fragile X Mental Retardation Protein
  • RNA
  • Cyclic AMP-Dependent Protein Kinases