Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage

Abstract

Neuroligins (NLGNs) are cell adhesion molecules located on the postsynaptic side of the synapse that interact with their presynaptic partners neurexins to maintain trans-synaptic connection. Fragile X syndrome (FXS) is a common neurodevelopmental disease that often co-occurs with autism and is caused by the lack of fragile X mental retardation protein (FMRP) expression. To gain an insight into the molecular interactions between the autism-related genes, we sought to determine whether FMRP controls the synaptic levels of NLGNs. We show evidences that FMRP associates with Nlgn1, Nlgn2, and Nlgn3 mRNAs in vitro in both synaptoneurosomes and neuronal cultures. Next, we confirm local translation of Nlgn1, Nlgn2, and Nlgn3 mRNAs to be synaptically regulated by FMRP. As a consequence of elevated Nlgns mRNA translation Fmr1 KO mice exhibit increased incorporation of NLGN1 and NLGN3 into the postsynaptic membrane. Finally, we show that neuroligins synaptic level is precisely and dynamically regulated by their rapid proteolytic cleavage upon NMDA receptor stimulation in both wild type and Fmr1 KO mice. In aggregate, our study provides a novel approach to understand the molecular basis of FXS by linking the dysregulated synaptic expression of NLGNs with FMRP.

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…1076 Neuron 101, March 20, 2019 Neuron Review 2013). Of note, NLGNs promote synaptic transmission (Varoqueaux et al, 2006) and are regulated by FMRP at synapses (Chmielewska et al, 2018;Darnell et al, 2011;Pasciuto and Bagni, 2014b).…”

Synaptopathology Involved in Autism Spectrum Disorder

“…FMRP plays a key role in the dynamic regulation of the synaptic proteome. FMRP associates with Nlgn1 , Nlgn2 and Nlgn3 mRNAs; consequently, Fmr1 KO leads to elevated local translation of Nlgn mRNAs and increased targeting of Nlgn1 and Nlgn3 to postsynaptic membranes (Chmielewska et al, 2018). FMRP binds to a G-rich region of PSD-95 mRNA, and together with microRNA miR-125a, plays an important role in the reversible inhibition of PSD-95 mRNA translation in neurons (Muddashetty et al, 2011; Stefanovic et al, 2015).…”

Spontaneous motor-behavior abnormalities in twoDrosophilamodels of neurodevelopmental disorders

“…For each of the 23 mouse genes whose transcripts bind FMRP (Chmielewska et al, 2019;Darnell et al, 2011;F€ ahling et al, 2009;Muddashetty et al, 2007;Zhang, Gaetano, Williams, Bassell, & Mihailescu, 2014), we searched PubMed and OMIM (Amberger, Bocchini, Scott, & Hamosh, 2019). For 17 of the human orthologs, we found evidence that mutations cause one or more neurodevelopmental disorders (Table S1).…”

“…Among the genes whose transcripts are known to be FMRP targets (Chmielewska et al, 2019;Darnell et al, 2011;Muddashetty et al, 2007) are 17 whose mutations cause Mendelian brain-development disorders, and most of those include ASD or "autistic features" as clinical phenotypes (Table S1). Remarkably, however, for the large majority of these, laboratory-based functional analyses of the mutations demonstrated that they are loss-of-function (LOF) alleles, often with haploinsufficiency and sometimes with dominantnegative characteristics.…”

“…By slowing ribosomal translocation on its mRNA targets, many of which encode synaptic proteins (Darnell & Klann, 2013), FMRP controls a large gene network necessary for normal neuronal differentiation and activity-dependent synaptic plasticity (Lee et al, 2003;Pfeiffer & Huber, 2009;Reeve et al, 2005;Schenck et al, 2003). Many genes with mutations causing neurodevelopmental disorders in humans, often with ASD as a phenotype, were independently identified in the mouse brain as having FMRP-targeted transcripts (Chmielewska, Kuzniewska, Milek, Urbanska, & Dziembowska, 2019;Darnell et al, 2011;Muddashetty, Keli c, Gross, Xu, & Bassell, 2007). The growing list now includes CAMK2A, CYFIP2, DLG4, GRIA2, GRIN2A, GRIN2B, KIF1A, LINGO1, MAP1B, NF1, NLGN1, NLGN2, NLGN3, NRXN1, PTEN, SHANK3, and TSC2 (Table S1).…”