SnapShot: FMRP Interacting Proteins

Abstract

The Fragile X syndrome, caused by the absence or mutation of fragile X mental retardation protein, FMRP, is a the common component of inherited intellectual disability and autism. This SnapShot surveys the protein interaction partners of FMRP, focusing on the cellular pathways in which they are involved.

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

“…However, abundance does not seem to be critical for FMRP effect: a clear set of 34% of FMRP bound mRNAs are most abundant in non-neuronal cell types, but their downregulation is strongest in neurons (cluster 2, Figure 5b-c, S3c-d). The impact on FMRP bound gene expression may be further mediated by cell type specific expression of protein partners of FMRP 5,76 , several of which are RNA binding proteins themselves. Many of these binding partners have functions in processes impacted in neurons or multiple cell types, such as splicing, cell signaling, vesicle transport and translation 76 .…”

“…The impact on FMRP bound gene expression may be further mediated by cell type specific expression of protein partners of FMRP 5,76 , several of which are RNA binding proteins themselves. Many of these binding partners have functions in processes impacted in neurons or multiple cell types, such as splicing, cell signaling, vesicle transport and translation 76 . We find no clear difference at RNA levels that suggests these genes contribute to the neuron-specific bound mRNA downregulation.…”

Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

“…FMRP is an RNA‐binding protein, abundantly expressed in the mammalian brain, where it binds 4% of the whole transcriptome, including its own message (Ashley et al , ). Since FMRP interacts with many other proteins, its absence has manifold consequences—in sum affecting neural development, synapse formation, and plasticity (Bassell & Warren, ; Darnell et al , ; Pasciuto & Bagni, ). A premutation syndrome (55–200 repeats) has also been reported with elevated FMR1 mRNA and reduced FMRP levels, where RNA toxicity is a possible underlying molecular mechanism (Garcia‐Arocena & Hagerman, ; Bagni et al , ).…”

Fragile X mental retardation protein: from autism to neurodegenerative disease

“…Since the identification of FMR1 as the causative gene for fragile X syndrome in 1991, studies have mainly focused on understanding the function of FMRP. More and more potential FMRP mRNA targets and interacting proteins have been identified in the mammalian brain, supporting the critical roles of FMRP in neurodevelopment, synaptic plasticity and other neurological disorders apart from fragile X syndrome (Wang et al, 2008b , 2012 ; Pasciuto and Bagni, 2014a ; Suhl et al, 2014 ).…”

“…These events include: Aberrant activation of PI3K-Akt-mTORC1 and MEK-ERK signaling pathways linked to cap-dependent translation result in altered synthesis of synaptic proteins; Oligomeric Aβ exposure disrupts the balance between tau kinase (GSK3β, CaMKII, Akt, Fyn, and ERK1/2) and phosphatase (PP2A, STEP, and PTEN) activities, inducing tau hyperphosphorylation and aggregation; Stimulating EphB2-Rac1/PAK1 signaling by Aβ oligomers induces cofilin phosphorylation and actin depolymerization, leading to actin network disorganization; Binding of Aβ oligomers to PrP C -mGluR5 activates Fyn kinase which phosphorylates not only tau, but also NR2B subunit of NMDARs, enhancing NMDAR activity and causing excitotoxicity; STEP is also activated, inactivates Fyn, and dephosphorylates AMPARs and NMDARs, resulting in endocytosis of glutamate receptors, a cellular process involves Arc, PSD-95, SAPAP, and other synaptic proteins. Purple proteins are those whose mRNAs are FMRP targets (Darnell and Klann, 2013 ; Pasciuto and Bagni, 2014b ; Santini and Klann, 2014 ); the blue ones are the interacting proteins of FMRP (Pasciuto and Bagni, 2014a ). Proteins with red lines around them indicate those that have been successfully manipulated either pharmacologically or genetically to reverse molecular, cellular and/or behavioral phenotypes in animal models of AD (Zhang et al, 2010 ; Malinow, 2012 ; Caccamo et al, 2014 ; Feld et al, 2014 ; Hamilton et al, 2014 ; Llorens-Martin et al, 2014 ) as well as ASDs (Goebel-Goody et al, 2012 ; Guo et al, 2012 ; Won et al, 2012 ; Darnell and Klann, 2013 ; Osterweil et al, 2013 ; Wang and Doering, 2013 ; Wang, 2014 ).…”