BC RNA mislocalization in the fragile X premutation

Abstract

Fragile X premutation disorder is caused by CGG triplet repeat expansions in the 5’ UTR of FMR1 mRNA. The question how expanded CGG repeats cause disease is a subject of continuing debate. Our work indicates that CGG-repeat structures compete with regulatory BC1 RNA for access to RNA transport factor hnRNP A2. As a result, BC1 RNA is mislocalized in vivo as its synapto-dendritic presence is severely diminished in brains of CGG-repeat knock-in animals (a premutation mouse model). Lack of BC1 RNA is known to cause seizure activity and cognitive dysfunction (Zhong et al., 2009; Chung et al., 2017; Iacoangeli et al., 2017). Our working hypothesis thus predicted that absence, or significantly reduced presence, of BC1 RNA in synapto-dendritic domains of premutation animal neurons would engender cognate phenotypic alterations. Testing this prediction, we established epileptogenic susceptibility and cognitive impairments as major phenotypic abnormalities of CGG premutation mice. In CA3 hippocampal neurons of such animals, synaptic release of glutamate elicits neuronal hyperexcitability in the form of mGluR-dependent prolonged epileptiform discharges. CGG-repeat knock-in animals are susceptible to sound-induced seizures and are cognitively impaired as revealed in the Attentional Set Shift Task. These phenotypic disturbances occur in young-adult premutation animals, indicating that a neurodevelopmental deficit is an early-initial manifestation of the disorder. The data are consistent with the notion that RNA mislocalization can contribute to pathogenesis.

Significance Statement The fragile X premutation finds expression in two distinct disease manifestations. Young premutation carriers may present with seizure activity and cognitive disturbances while advanced-age patients may experience intention tremor and gait ataxia, a condition known as FXTAS. In contrast to FXTAS, the early-onset phase of fragile X premutation disorder remains poorly understood. We discovered that in brains of CGG-repeat knock-in animals (a premutation mouse model), regulatory BC1 RNA is mislocalized as its presence at synapto-dendritic domains is severely diminished. Lack of BC1 RNA is known to cause epileptogenesis and cognitive dysfunction, and we report that such phenotypic alterations are hallmarks of young premutation animals. The data are congruous with a potential role of RNA localization impairments in pathogenesis.