Abstract
Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.
Highlights
The Fragile X mental retardation 1 gene (FMR1) is located on the long arm of the X-chromosome at Xq27.3 and codes for the fragile X mental retardation protein (FMRP), which is necessary for normal brain development and synaptic plasticity [1,2,3,4,5]
Expected, based on silencing of FMR1 expression in fragile X syndrome (FXS), no increased methylation of the Fmr1 gene has been found even with longer CGG repeat expansions. These mice models exhibit much of the pathology seen in affected fragile X premutation (FPM) carriers and in fragile X-associated tremor/ataxia syndrome (FXTAS), including increased expression of Fmr1 mRNA, decreased FMRP, ubiquitin-positive intranuclear inclusions (Figure 3) and evidence for motor and spatial processing deficits [21]
Electrophysiological findings GABA/glutamate imbalance and abnormal synaptic network activity The origin of pathology in FXS and in some FPM carriers, with or without FXTAS mutations, is the presence of a CGG repeat expansion on FMR1, raising the possibility that some of the same molecular pathways could be affected in both disorders, and those associated with glutamatergic signaling in particular [1,74,90,91]
Summary
The Fragile X mental retardation 1 gene (FMR1) is located on the long arm of the X-chromosome at Xq27.3 and codes for the fragile X mental retardation protein (FMRP), which is necessary for normal brain development and synaptic plasticity [1,2,3,4,5]. Expected, based on silencing of FMR1 expression in FXS, no increased methylation of the Fmr gene has been found even with longer CGG repeat expansions (for example, >300) As described below, these mice models exhibit much of the pathology seen in affected FPM carriers and in FXTAS, including increased expression of Fmr mRNA, decreased FMRP, ubiquitin-positive intranuclear inclusions (Figure 3) and evidence for motor and spatial processing deficits [21]. Electrophysiological findings GABA/glutamate imbalance and abnormal synaptic network activity The origin of pathology in FXS and in some FPM carriers, with or without FXTAS mutations, is the presence of a CGG repeat expansion on FMR1, raising the possibility that some of the same molecular pathways could be affected in both disorders, and those associated with glutamatergic signaling in particular [1,74,90,91] This is in spite of differences in the causal molecular underpinnings in the disorders, and the lack of FMRP expression in FXS versus the overexpression of FMR1 mRNA in the FPM and FXTAS. The data did not show translation product from the +0 (that is, CGG, polyarginine) reading frame, but some, albeit less efficient, translation in the +2 (that is, GCG, polyalanine) reading frame was observed [20]
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