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Updated: Jun 6, 2025

Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
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DJ-1-mediated repression of the RNA-binding protein FMRP is predicted to impact known Alzheimer's disease-related

Ayse Uneri1, Colin J McArdle1, Zhiyong Deng1

  • 1Department of Translational Neuroscience, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.

Journal of Alzheimer'S Disease : JAD
|November 29, 2024
PubMed
Abstract

Insights

RNA-binding proteins DJ-1 and FMRP are implicated in Alzheimer's disease (AD) synaptic dysfunction. Their altered interactions impact mRNA translation and protein expression, potentially driving AD-related pathways.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • RNA-binding proteins (RBPs) regulate synaptic function and homeostasis.
  • Dysfunctional RBPs contribute to neurological disorders like Alzheimer's disease (AD).
  • The role of RBPs in AD pathogenesis remains largely unexplored.

Purpose of the Study:

  • To investigate alterations in RBP-mRNA interactions in AD.
  • To determine the impact of these changes on the AD-related proteome.
  • To identify novel therapeutic targets for AD.

Main Methods:

  • RNA-immunoprecipitation to study RBP-mRNA interactions.
  • Surface Sensing of Translation - Proximity Ligation Assay (SUnSET-PLA) and western blotting to quantify translation and protein expression.
  • Bioinformatic analysis to link AD pathways to RBPs DJ-1 and FMRP (Fragile X messenger ribonucleoprotein 1).

Main Results:

  • Oligomeric DJ-1 exhibits reduced mRNA binding dynamics in AD synapses.
  • DJ-1 associates with FMRP mRNA (Fmr1), decreasing synaptic FMRP expression in AD.
  • Aberrant DJ-1 and FMRP expression are predicted to upregulate AD-related pathways (thyroid hormone, autophagy, ubiquitin-mediated proteolysis).

Conclusions:

  • DJ-1 and FMRP are novel therapeutic targets for AD.
  • Modulating DJ-1 and FMRP may restore neurobiological mechanisms in AD.
  • This study highlights the critical role of RBPs in AD synaptic dysfunction.
Keywords:
Alzheimer's diseaseDJ-1KEGG pathwaysRNA networksRNA-binding proteinsautophagyfragile x messenger ribonucleoprotein (FMRP)synapsethyroid hormone stimulating pathwayubiquitin mediated proteolysis

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