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

Award Number: R03MH135518
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $156,500 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	1	12/22/2023	NEW	$156,500
														Subtotal = $156,500

Grand Total All Awards = $156,500

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

Award Number: R03MH135518

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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