Exaggerated translational repression of FMRP in AD synapses

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive cognitive disorder where synapse loss has been well documented. Identifying and restoring molecular targets that are involved in synapse loss is crucial in restoring balanced synaptic function and communication. FMRP is an RNA‐binding protein that is essential protein for synapse formation and stability, and is understudied in AD. Understanding how FMRP may be dysregulated at the synaptic level in AD is integral in developing treatments for AD.MethodRNA‐immunoprecipitation of DJ‐1 was performed to detect whether DJ‐1 associates with the mRNA coding for FMRP. Synaptoneurosomes and postsynaptic densities we isolated from AD rodent model APP/PS1deltaE9 and postmortem human AD patients, as well as from appropriate controls, and performed Western blotting to analyze FMRP protein expression. SUnSET‐PLA assay was utilized to determine de novo synthesis of FMRP in DJ‐1 overexpression.ResultDJ‐1, which is an RNA‐binding protein that is overexpressed in AD synapses, associates with Fmr1, the mRNA coding for the protein FMRP. FMRP expression is decreased in AD synapses, as well as postsynaptic densities. When DJ‐1 is overexpressed in WT cultures, there is less newly synthesized FMRP.ConclusionHere, we show that DJ‐1 associates with Fmr1, which codes for another RNA‐binding protein, FMRP. DJ‐1 and FMRP are aberrantly expressed in AD synapses. DJ‐1 is overexpressed in AD synapses while FMRP is reduced. Furthermore, when DJ‐1 is overexpressed in WT cultures, FMRP synthesis is reduced, suggesting that DJ‐1 is a translational repressor of FMRP. Therefore, the reduction of FMRP in AD synapses are due to overexpression of DJ‐1, and the rescue of FMRP expression could potentially rescue synaptic loss in AD.