FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

Abstract

There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (<i>FMR1</i>) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (<i>CYFIP1</i>) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of <i>FMR1</i> and <i>CYFIP1</i> to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.

Genetic association of FMRP targets with psychiatric disorders

“…Moreover, binding by FMRP may not equate to translational repression in the cell, which requires additional contribution from binding partners CYFIP1 and eIF4E, within a protein complex[ 5 ]. As well as regulating protein synthesis, FMRP is reported to have other roles, including the mediation of mRNA stability and dendritic transport [ 9 , 89 , 90 ]. Each of these processes may be relevant to psychiatric risk and this line of research will benefit from further validation of FMRP-regulated mRNAs.…”

Loss of cytoplasmic FMR1‐interacting protein 2 (CYFIP2) induces browning in 3T3‐L1 adipocytes via repression of GABA‐BR and activation of mTORC1

“…In recent years, CYFIP2 many studies have revealed an extensive array of synaptic roles, far beyond its initial characterization as a binding partner to FMRP. 16 Several studies reported that the loss of FMRP reduced the levels of lipids, including cholesterol, and supported the possible functions of FMRP in controlling glucose and lipid metabolism. [17][18][19] Moreover, the Fmr1/Fxr2 double knockout (KO) mice displayed increased glucose tolerance and insulin sensitivity, reduced adiposity, and reduced circulating glucose.…”

“…Importantly, CYFIP2 is a component of the WAVE regulatory complex, a key regulator of the actin cytoskeleton, 15 suggesting that CYFIP2 is involved in the dendritic spine phenotype of Fragile X syndrome (FXS). In recent years, CYFIP2 many studies have revealed an extensive array of synaptic roles, far beyond its initial characterization as a binding partner to FMRP 16 . Several studies reported that the loss of FMRP reduced the levels of lipids, including cholesterol, and supported the possible functions of FMRP in controlling glucose and lipid metabolism 17–19 .…”

Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network

“…Initially, mass spectrometry analyses of murine brains and cultured cells showed that FMRP is mainly phosphorylated between the amino acid residues 483 and 521. Within this sequence, primary phosphorylation takes place at the conserved serine 499, which subsequently triggers phosphorylation of the nearby residues Ser489, Ser493, Ser496, Ser503, Ser510, and Ser513 [49,50]. Strict regulation of FMRP phosphorylation is crucial for controlling its ability to modulate the translation process.…”