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Mouse Models of Fragile X-Associated Tremor Ataxia
  1. Robert F. Berman, PhD*,
  2. Rob Willemsen, PhD
  1. From the *Department of Neurological Surgery and the Neurotherapeutics Research Institute, University of California Davis, Davis, CA; and †CBG Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
  1. Received April 30, 2009.
  2. Accepted for publication May 18, 2009.
  3. Reprints: Robert F. Berman, PhD, Department of Neurological Surgery, University of California Davis, Davis, CA 95616. E-mail: rfberman{at}ucdavis.edu.
  4. This research was supported by NIH-NINDS grants NS062411 and RR024922, NIH Roadmap Initiative UL1 1 DE019583-02, NIDCR, and the symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236).

Abstract

Objective To describe the development of mouse models of fragile X-associated tremor/ataxia (FXTAS) and the behavioral, histological and molecular characteristics of these mice.

Method This paper compares the pathophysiology and neuropsychological features of FXTAS in humans to the major mouse models of FXTAS. Specifically, the development of a transgenic mouse line carrying an expanded CGG trinucleotide repeat in the 5'-untranslated region (5'-UTR) of the Fmr1 gene is described along with a description of the characteristic intranuclear ubiquitin-positive inclusions and the behavioral sequella observed in these mice.

Results CGG KI mice model many of the important features of FXTAS, although some aspects are not well modeled in mice. Aspects of FXTAS that are modeled well include elevated levels of Fmr1 mRNA, reduced levels of Fmrp, the presence of intranuclear inclusions that develop with age and show similar distributions within neurons, and neuropsychological and cognitive deficits, including poor motor function, impaired memory and evidence of increased anxiety. Features of FXTAS that are not well modeled in these mice include intentional tremors that are observed in some FXTAS patients but have not been reported in CGG KI mice. In addition, although intranuclear inclusions in astrocytes are very prominent in FXTAS, there are relatively few observed in CGG KI mice. A number of additional features of FXTAS have not been systematically examined in mouse models yet, including white matter disease, hyperintensities in T2-weighted magnetic resonance imaging, and brain atrophy, although these are currently under investigation in our laboratories.

Conclusions The available mouse model has provided valuable insights into the molecular biology and pathophysiology of FXTAS and will be particularly useful for developing and testing new therapeutic treatments in the future.

Key Words
  • FXTAS
  • mouse models
  • Fmr1
  • Fmrp; fragile X
  • ubiquitin
  • neurodegenerative disorder

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