Fragile X mental retardation protein: from autism to neurodegenerative disease.

Abstract

Fragile X mental retardation protein (FMRP) is a RNA binding protein, the absence of which due to silencing of the FMR1 gene causes fragile X syndrome, an X-linked neurodevelopmental disorder (Bassell and Warren, 2008; Bhakar et al., 2012; Santoro et al., 2012). FMRP regulates the transport, stability and translation of its mRNA targets. Loss of FMRP alters translational control and receptor-mediated signaling pathways, leading to aberrant dendritic spine dynamics, synaptic dysfunction and behavioral phenotypes in fragile X syndrome (Wang et al., 2012; Sidorov et al., 2013; Suhl et al., 2014). 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). Fragile X syndrome, the most common monogenic cause of autism spectrum disorders (ASDs), has been leading the way for better understanding of autism and other neurodevelopmental disorders (Belmonte and Bourgeron, 2006; Bhakar et al., 2012; Banerjee et al., 2014; Cook et al., 2014). Clinically, a substantial proportion of children with fragile X syndrome meets diagnostic criteria for ASDs (Budimirovic and Kaufmann, 2011). Genetically and biologically, many of the neuronal targets of FMRP overlap with genes associated with ASDs, suggesting the common pathways that are dysregulated and might be potential therapeutic targets for these neurodevelopmental disorders (Auerbach et al., 2011; Zoghbi and Bear, 2012; Darnell and Klann, 2013). Interestingly, studies in recent years have further revealed that FMRP regulates a multitude of synaptic proteins and components of signaling pathways that not only affect neurodevelopment, but also contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer disease (AD), the leading cause for dementia in the elderly (Malter et al., 2010; Sokol et al., 2011; Westmark et al., 2011; Hamilton et al., 2014). FMRP may play a pivotal role in the association between neurodevelopmental and neurodegenerative disorders across lifespan.