Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation

• Authors: Vijayalaxmi C. Nalavadi, Emory University; Ravi S. Muddashetty, Emory University; Christina Gross, Emory University; Gary Bassell, Emory University
• Journal Title: Journal of Neuroscience Nursing
• Volume: Volume 32, Number 8
• Publisher: Lippincott, Williams & Wilkins | 2012-02-22, Pages 2582-2587
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1523/JNEUROSCI.5057-11.2012
• Subjects: Biology, Neuroscience; Biology, Cell

Abstract

Fragile X Syndrome is caused by the loss of FMRP, which represses and reversibly regulates the translation of a subset of mRNAs in dendrites. Protein synthesis can be rapidly stimulated by mGluR-induced and PP2A-mediated dephosphorylation of FMRP, which is coupled to the dissociation of FMRP and target mRNAs from miRISC complexes. Here, we report the rapid ubiquitination and UPS mediated degradation of FMRP in dendrites upon DHPG stimulation in cultured rat neurons. Using inhibitors to PP2A and FMRP phosphomutants, degradation of FMRP was observed to depend on its prior dephosphorylation. Translational induction of an FMRP target, PSD-95 mRNA, required both PP2A and UPS. Thus, control of FMRP levels at the synapse by dephosphorylation-induced and UPS mediated degradation provides a mode to regulate protein synthesis.