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

Renate K. Hukema, Ronald A M Buijsen, Martijn Schonewille, Chris Raske, Lies Anne W F M Severijnen, Ingeborg Nieuwenhuizen-Bakker, Rob F M Verhagen, Lisanne van Dessel, Alex Maas, Nicolas Charlet-Berguerand, Chris I. De Zeeuw, Paul J Hagerman, Robert F Berman, Rob Willemsen

Research output: Contribution to journalArticle

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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of the fragile X-premutation, who have an expanded CGG repeat in the 5'-UTR of the FMR1 gene. FXTAS is characterized by progressive development of intention tremor, ataxia, parkinsonismand neuropsychological problems. The disease is thought to be caused by a toxic RNA gain-of-function mechanism, and the major hallmark of the disease is ubiquitin-positive intranuclear inclusions in neurons and astrocytes. We have developed a new transgenic mouse model in which we can induce expression of an expanded repeat in the brain upon doxycycline (dox) exposure (i.e. Tet-On mice). This Tet-On model makes use of the PrP-rtTA driver and allows us to study disease progression and possibilities of reversibility. In these mice, 8 weeks of dox exposure was sufficient to induce the formation of ubiquitin-positive intranuclear inclusions, which also stain positive for the RAN translation product FMRpolyG. Formation of these inclusions is reversible after stopping expression of the expanded CGG RNA at an early developmental stage. Furthermore, we observed a deficit in the compensatory eye movements of mice with inclusions, a functional phenotype that could be reduced by stopping expression of the expanded CGG RNA early in the disease development. Taken together, this study shows, for the first time, the potential of disease reversibility and suggests that early intervention might be beneficial for FXTAS patients.

Original languageEnglish (US)
Pages (from-to)4948-4957
Number of pages10
JournalHuman Molecular Genetics
Volume24
Issue number17
DOIs
StatePublished - 2015

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Intranuclear Inclusion Bodies
Doxycycline
RNA
Ubiquitin
Poisons
5' Untranslated Regions
Tremor
Ataxia
Eye Movements
Astrocytes
Neurodegenerative Diseases
Transgenic Mice
Disease Progression
Coloring Agents
Phenotype
Neurons
Fragile X Tremor Ataxia Syndrome
Neuropathology
Brain
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Hukema, R. K., Buijsen, R. A. M., Schonewille, M., Raske, C., Severijnen, L. A. W. F. M., Nieuwenhuizen-Bakker, I., ... Willemsen, R. (2015). Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. Human Molecular Genetics, 24(17), 4948-4957. https://doi.org/10.1093/hmg/ddv216

Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. / Hukema, Renate K.; Buijsen, Ronald A M; Schonewille, Martijn; Raske, Chris; Severijnen, Lies Anne W F M; Nieuwenhuizen-Bakker, Ingeborg; Verhagen, Rob F M; van Dessel, Lisanne; Maas, Alex; Charlet-Berguerand, Nicolas; De Zeeuw, Chris I.; Hagerman, Paul J; Berman, Robert F; Willemsen, Rob.

In: Human Molecular Genetics, Vol. 24, No. 17, 2015, p. 4948-4957.

Research output: Contribution to journalArticle

Hukema, RK, Buijsen, RAM, Schonewille, M, Raske, C, Severijnen, LAWFM, Nieuwenhuizen-Bakker, I, Verhagen, RFM, van Dessel, L, Maas, A, Charlet-Berguerand, N, De Zeeuw, CI, Hagerman, PJ, Berman, RF & Willemsen, R 2015, 'Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS', Human Molecular Genetics, vol. 24, no. 17, pp. 4948-4957. https://doi.org/10.1093/hmg/ddv216
Hukema RK, Buijsen RAM, Schonewille M, Raske C, Severijnen LAWFM, Nieuwenhuizen-Bakker I et al. Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. Human Molecular Genetics. 2015;24(17):4948-4957. https://doi.org/10.1093/hmg/ddv216
Hukema, Renate K. ; Buijsen, Ronald A M ; Schonewille, Martijn ; Raske, Chris ; Severijnen, Lies Anne W F M ; Nieuwenhuizen-Bakker, Ingeborg ; Verhagen, Rob F M ; van Dessel, Lisanne ; Maas, Alex ; Charlet-Berguerand, Nicolas ; De Zeeuw, Chris I. ; Hagerman, Paul J ; Berman, Robert F ; Willemsen, Rob. / Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 17. pp. 4948-4957.
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AU - Charlet-Berguerand, Nicolas

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