Mouse models of fragile X-associated tremor ataxia

Robert F Berman, Rob Willemsen

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Objective: To describe the development of mouse models of fragile Xassociated 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.

Original languageEnglish (US)
Pages (from-to)837-841
Number of pages5
JournalJournal of Investigative Medicine
Volume57
Issue number8
DOIs
StatePublished - Dec 2009

Fingerprint

Tremor
Ataxia
Trinucleotide Repeats
Molecular biology
Intranuclear Inclusion Bodies
5' Untranslated Regions
Magnetic resonance
Ubiquitin
Neurons
Brain
Genes
Trinucleotide Repeat Expansion
Imaging techniques
Data storage equipment
Messenger RNA
Leukoencephalopathies
Testing
Astrocytes
Transgenic Mice
Atrophy

Keywords

  • Fmr1
  • Fmrp
  • Fragile X
  • FXTAS
  • Mouse models
  • Neurodegenerative disorder
  • Ubiquitin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mouse models of fragile X-associated tremor ataxia. / Berman, Robert F; Willemsen, Rob.

In: Journal of Investigative Medicine, Vol. 57, No. 8, 12.2009, p. 837-841.

Research output: Contribution to journalArticle

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