# Fragile X messenger ribonucleoprotein-1 mediated regulation of the Clathrin-Associated Adaptor Complex Protein-2 (AP2)

> **NIH NIH R03** · EMORY UNIVERSITY · 2024 · $156,500

## Abstract

Fragile x syndrome (FXS) is the most common form of inherited intellectual disability and monogenic cause of
autism. FXS is caused by silencing of the FMR1 gene encoding FMRP, the fragile x messenger
ribonucleoprotein 1. FMRP is a mRNA binding protein known to regulate mRNA translation, including local
protein synthesis important for synapse development and function. Impaired surface expression of glutamate
receptors and ion channels are believed to contribute to altered synaptic plasticity and neuronal
hyperexcitability, respectively, in FXS. Recent work suggests even more global defects in membrane trafficking
and the endocytic pathway may occur at synapses in FXS. A critical gap is lack of understanding of underlying
mechanisms for how FMRP might regulate endocytosis and membrane protein surface expression to control
neuronal function. Our central hypothesis is that FMRP directly regulates endocytic machinery via local
translation and/or non-canonical mechanisms to control membrane surface protein expression. In this
application, we investigate a greatly neglected area of the Clathrin-Associated Adaptor Complex Protein-2
dependent regulatory mechanism at the translational level by FMRP. This is a new concept as AP2 regulation
studies have been traditionally focused on adaptor post-translational modification with very little work on post-
transcriptional mechanisms for any adapter protein by any RNA binding protein. Aim 1 will test the hypothesis
that FMRP is a negative regulator of the Clathrin-Associated Adaptor Complex Protein-2 (AP2) mediated
endocytosis. We propose to investigate the effects of FMRP deficiency on AP2 subunit translation, expression,
and synaptic localization in mouse cortical neurons. As AP2 is known to be required for regulation of AMPA
receptor endocytosis, we will investigate whether exaggerated internalization of AMPA receptors in FXS
neurons can be rescued by modulating aberrant expression of AP2 subunits.
Aim 2 will test the hypothesis
that loss of FMRP has broad effects on the surface expression of membrane proteins and endocytosis. We
propose to use a mass spectrometry approach for an unbiased characterization of the surface proteome in WT
versus FMR1 KO neurons. Lastly, we will investigate whether modulating aberrant expression of AP2 subunits
using genetic and pharmacologic strategies can normalize defects in the expression of surface proteins
including ion channels. The proposed studies will identify new biology for FMRP mediated control of the
dynamics of membrane protein surface expression via AP2 subunit regulation. We will broadly identify the
specific surface proteins adversely affected in FXS model neurons to guide future research. This research has
implications for future development of therapeutic strategies that may target AP2 to correct for altered
membrane protein surface expression contributing to impairments in synaptic plasticity and neuronal
hyperexcitability in FXS.

## Key facts

- **NIH application ID:** 10817391
- **Project number:** 1R03MH135518-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** GARY J BASSELL
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $156,500
- **Award type:** 1
- **Project period:** 2024-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817391

## Citation

> US National Institutes of Health, RePORTER application 10817391, Fragile X messenger ribonucleoprotein-1 mediated regulation of the Clathrin-Associated Adaptor Complex Protein-2 (AP2) (1R03MH135518-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10817391. Licensed CC0.

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