What has been learned from mouse models of the Fragile X Premutation and Fragile X-associated tremor/ataxia syndrome?

Foote, Molly; Careaga, Milo; Berman, Robert F.

doi:10.1080/13854046.2016.1158254

Cited by 6 publications

(4 citation statements)

References 63 publications

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“…Subsequent hypermetylation results in transcriptional silencing, and partial or full loss of expression of the fragile X mental retardation protein (FMR1 protein or FMRP). In the general population there are 5-44 CGG repeats, in the fragile X premutation 55-200 and above 200 in the fragile X full-mutation (Foote et al, 2016;.…”

Section: Fragile X Syndrome Fmr1 Protein and Bc1 Non-protein-coding Rnamentioning

confidence: 99%

Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome

Juczewski

Richthofen

Bagni

et al. 2016

Neurobiology of Disease

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Section: Fragile X Syndrome Fmr1 Protein and Bc1 Non-protein-coding Rnamentioning

confidence: 99%

Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome

Juczewski

Richthofen

Bagni

et al. 2016

Neurobiology of Disease

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“…The behavioral tests used in the present study for GFAP-CGG99-EGFP mice were selected to examine similar neurobehavioral deficits in FXTAS, including anxiety in the elevated plus-maze, ataxia and motor deficits in the ladder rung test, rotarod and TredScan apparatus, and cognitive loss using contextual fear conditioning [20].…”

Section: Methodsmentioning

confidence: 99%

“…The CGG KI mouse model of FXTAS shows similar neurobehavioral features that appear to be similar to those in FXTAS [20]. These include gait ataxia and visuomotor deficits in the ladder-rung [31] and rotarod tests [54], anxiety in the open field [10] and cognitive impairment [30, 32].…”

Section: Introductionmentioning

confidence: 99%

Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology

Wenzel

Murray

Haify

et al. 2019

acta neuropathol commun

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The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5′-untranslated region of the fragile X mental retardation 1 ( FMR1 ) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence, were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of FMRpolyG, and deficits in motor function. Electronic supplementary material The online version of this article (10.1186/s40478-019-0677-7) contains supplementary material, which is available to authorized users.

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“…The discovery of FXTAS revived interest in the PM mouse models, given that these KI mice might provide crucial insights into the molecular mechanisms that underlie FXTAS with aging. Both KI models, CGG dut and CGG nih , showed elevated Fmr1 mRNA levels, reduced Fmrp production, the presence of ubiquitin-positive intranuclear inclusions throughout the brain and specific behavioral deficits, including late-onset ataxia, memory impairment and impaired motor performance, all key features of FXTAS ( Entezam et al, 2007 ; Willemsen et al, 2003 ; reviewed in Foote et al, 2016 ). Importantly, RAN translation occurs in CGG dut KI mice, together with the accumulation of FMRpolyG-positive intranuclear neuronal inclusions ( Fig.…”

Section: Pm Mouse Models Of Fxtasmentioning

confidence: 99%

Mouse models of fragile X-related disorders

Willemsen

Kooy

2023

Disease Models &Amp; Mechanisms

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The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5′ untranslated region of the FMR1 gene or by mutations in the coding sequence of this gene. Two categories of pathological CGG repeats are associated with these disorders, full mutation alleles and shorter premutation alleles. Individuals with full mutation alleles develop fragile X syndrome, which causes autism and intellectual disability, whereas those with premutation alleles, which have shorter CGG expansions, can develop fragile X-associated tremor/ataxia syndrome, a progressive neurodegenerative disease. Thus, fragile X-related disorders can manifest as neurodegenerative or neurodevelopmental disorders, depending on the size of the repeat expansion. Here, we review mouse models of fragile X-related disorders and discuss how they have informed our understanding of neurodegenerative and neurodevelopmental disorders. We also assess the translational value of these models for developing rational targeted therapies for intellectual disability and autism disorders.

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What has been learned from mouse models of the Fragile X Premutation and Fragile X-associated tremor/ataxia syndrome?

Cited by 6 publications

References 63 publications

Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome

Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome

Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology

Mouse models of fragile X-related disorders

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