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Review
. 2016 Oct;15(5):611-22.
doi: 10.1007/s12311-016-0797-6.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice

Molly Foote  1 , Gloria Arque  2 , Robert F Berman  3 , Mónica Santos  4
Affiliations
Review

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice

Molly Foote et al. Cerebellum. 2016 Oct.

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some carriers of the fragile X premutation (PM). In PM carriers, there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the fragile X mental retardation protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that causes PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically, we will discuss the construct, face, and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms, and potential treatments.

Keywords: CGG trinucleotide repeat; Fragile X mental retardation (FMR1) gene; Fragile X premutation; Fragile X-associated tremor/ataxia syndrome (FXTAS); Mouse models; Neurodegenerative disorder.

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Conflict of interest statement

Compliance with Ethical Standards: Conflict of Interest: The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Mouse models of the fragile X premutation. A) Schematic drawings representing the genetic constructs designed for each of the PM mouse models: Dutch (21), NIH CGG KI (24) and the Inducible PrP-CGG90 mouse model (26). Both the Dutch mouse model has an intact mouse promoter followed by a human genetic sequences flanking the inserted CGG repeat expansion upstream of the mouse Fmr1 gene. The NIH CGG KI mouse has an in vitro-generated CGG repeat tract inserted to replace mouse CGG8 also keeping the mouse Fmr1 gene and promotor intact. The Inducible mouse transgenically expresses the CGG repeat expansion outside the context of the Fmr1 gene in the mice which is activated by doxycycline (dox). B) Summary of the molecular pathological changes reported in each mouse model. The Dutch and NIH CGG KI mice show similar mRNA and FMRP expression changes, however only the Dutch and Inducible mouse models also produce the toxic FMRpolyG peptide. C) Representative images showing immunodetection for ubiquitin-positive intranuclear inclusions, the hallmark histopathology of PM and FXTAS, in brain tissue from each of the mouse models. Images were reprinted and/or modified with copyright permissions (21, 22, 24, 26)
Figure 2
Figure 2
Brain FMR1 mRNA levels in the Dutch CGG KI mice with Low (85-102) and High CGG (142-183) trinucleotide repeat lengths at embryonic ages 11.5 and 14.5 days and postnatal days P0, P7 and P18 compared to wildtype mice (WT). The ordinate represents mean fold-changes from WT (+ SE). *p<0.05, **p<0.01)
Figure 3
Figure 3
Brain FMRP levels in the Dutch CGG KI mice with Low (85-102) and High (142-183) CGG trinucleotide repeat lengths at embryonic ages 11.5 and 14.5 days and postnatal days P0, P7 and P18 compared to wildtype mice (WT). The ordinate represents percent change (% +SE) from wildtype (WT). *p<0.05, **p<0.01)
Figure 4
Figure 4
Wahlsten neurodevelopmental neonatal test battery for motor and sensory functions from postnatal day 8 (P8) through postnatal day 18 (P18) on Dutch CGG KI mice. Average scores for motor (e.g., forelimb and hind limb grasp, righting reflex, etc) and sensory (eye opening, auditory startle, etc) functions were calculated as described previously (Wahlsten, 1974). *P<0.05 versus WT.
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References

    1. Bagni C, Greenough WT. From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci. 2005;6(5):376–87. - PubMed
    1. Weiler IJ, Irwin SA, Klintsova AY, Spencer CM, Brazelton AD, Miyashiro K, et al. Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc Natl Acad Sci U S A. 1997;94(10):5395–400. - PMC - PubMed
    1. Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67(6):1047–58. - PubMed
    1. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905–14. - PubMed
    1. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57(1):127–30. - PubMed

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