A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Abstract

Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders.

Keywords: ASDs; ERK; FMRP; FXS; MNK; TSC; mGluRs; mRNA metabolism; mTOR; synaptopathies.

Figure 1.. Simplified Model of the mTOR-ERK1/2-WAVE Signaling Pathways at Synapses

mGluRs mediate activation of PI3K via scaffolding proteins such as PIKE and HOMER, leading to the activation of AKT and inhibition of TSC1-TSC2 complex. TSC2 inhibition of RHEB activates mTORC1, resulting in FMRP phosphorylation by S6 kinase. The phosphorylation status affects its RNA-binding properties as well as its translational regulation. FMRP interacts with the initiation factor eIF4E and regulates translational through the specific eIF4E-binding protein CYFIP1. In Fmr1 KO mice and FXS individuals, PI3K is upregulated, leading to an increased mTOR phosphorylation, culminating in an increased protein synthesis. mTORC2 has a central role in actin remodeling through its actions on RAC1 and LIMK phosphorylation on the actin-depolymerizing factor cofilin (CFL). Proteins encoded by genes associated with ASDs (SFARI database, https://gene.sfari.org) are colored in orange.

Figure 2.. Shared Genes among FMRP Targets, Axonal/Dendritic Transcriptome, and ASDs

Among the 1,842 identified putative FMRP targets, 271 are in common with ASD genes and 859 are in common with the axonal/dendritic transcriptome. Moreover, 146 genes are shared with all three classes. 1,842 FMRP targets are based on the work from Ascano et al. (2012); Brown et al. (2001); Chen et al. (2003); Darnell et al. (2011); Miyashiro et al. (2003) and the list by Ascano et al. (2012) filtered for brain expression. 1,065 ASD genes are from the SFARI database, AutDB database (Pereanu et al., 2018), and Mahfouz et al. (2015). 5,028 genes from the axonal and dendritic localized transcriptome are based on the work by Cajigas et al. (2012) and Gumy et al. (2011).

Figure 3.. FMRP Differently Recognizes Neuronal mRNAs

Four principal mechanisms by which FMRP recognizes mRNA targets. (A) FMRP recognizes G-quartet structure and G-rich regions of the target mRNA. (B) FMRP binds specific RNA recognition elements (RREs) such as ACUK and WGGA (Ascano et al., 2012). (C and D) FMRP binds mRNA targets indirectly through either the small non-coding RNA brain cytoplasmic RNA 1 (BC1) (C) or microRNAs (miRNAs) (D). Modified from Bagni and Greenough (2005).

Figure 4.. A Schematic of the Process and Main Regulatory Machinery of the Autophagy

The metabolic sensors mTOR and AMPK are the main regulators of autophagy activation. mTORC1 phosphorylates ULK-1, inhibiting autophagy. In condition of nutrient depletion and cellular stress, AMPK phosphorylates and activates ULK-1, promoting phosphorylation and activation of Beclin-1, a critical step in the nucleation phase of autophagy. Cytoplasmic material is engulfed by double membranes forming a cup-shaped structure called phagophore. Beclin-1 promotes LC3-I lipidation to generate its lipidated form LC3-II, enabling elongation of the limiting membrane of the phagophore and formation of autophagosomes. Autophagosomes require protein adaptors such as p62 to deliver proteins and organelles to lysosomes for degradation in the autolysosome. FMRP inhibits mTORC1, and Fmr1 KO mice show an overactivation of mTORC1 with consequent hyperphosphorylation of ULK1/2 and downregulation of autophagy (Yan et al., 2018).