Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

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.

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

“…Several reports favor a pathogenic mechanism that involves the effects of the premutation mRNA. These mRNA repeat tracks may lead to sequestration of proteins that bind to the repeat, thus losing their potential to function properly (reviewed in (19)). Also, these long repeat tracks may cause repeat associated non-AUG (RAN) translation, leading to a toxic polygutamine or polyalanine products (43).…”

“…Several mechanisms have been put forward to explain how premutation alleles might trigger neurodegeneration, including a gain-of-function (toxicity) RNA (15,16), sequestration of factors important for cell function by the "excess" of FMR1 transcript (17,18) and translation of aberrant and toxic polyGFMR1 protein (19). While bioenergetics deficits-evidenced as mitochondrial dysfunction, abnormal mitochondrial morphology and/or dynamics-have been observed in samples from carriers emotional and neurocognitive issues (2)(3)(4)(5), primary ovarian insufficiency (6) and later in life the neurodegenerative disorder fragile X-associated tremor/ ataxia syndrome (FXTAS) (1), characterized by progressive gait ataxia, intention tremor (7,8), cognitive and…”

Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS

“…However, previous mouse models did not make it possible to address questions concerning the possible reversibility of FXTAS or to elucidate critical periods in the natural history of the disease (13). In order to address such questions, we describe the successful development and initial characterization of an inducible mouse model for the fragile X-premutation and FXTAS.…”

“…In our knock-in mouse model, the murine 8CGG repeat has been replaced by homologous recombination in ES cells with a human expanded 98CGG (12). This model recapitulates many of the features seen in human FXTAS: not only increased expression of Fmr1 mRNA, decreased levels of FMRP and intranuclear aggregates in neurons and astrocytes, but also poor motor function, impaired memory and progressive spatial processing deficits (13). Recently, we reported initial findings in our new Tet-On doxycycline-inducible mouse model for FXTAS (14).…”

Current research, diagnosis, and treatment of fragile X-associated tremor/ataxia syndrome

“…Animal models for the fragile X premutation have been developed to understand the molecular mechanism of FXTAS (97). Mice models have shown increased FMR1 mRNA levels, decreased FMRP levels and ubiquitin-positive intranuclear inclusions (98).…”