Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS
| Autor: | Robert F. Berman, Nicolas Charlet-Berguerand, Rob F M Verhagen, Chris Raske, Lies Anne Severijnen, Lisanne van Dessel, Alex Maas, Rob Willemsen, Ronald A.M. Buijsen, Paul J. Hagerman, Renate K. Hukema, Ingeborg Nieuwenhuizen-Bakker, Martijn Schonewille, Chris I. De Zeeuw |
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| Přispěvatelé: | Clinical Genetics, Neurosciences, Clinical Chemistry, Internal Medicine, Molecular Genetics, Netherlands Institute for Neuroscience (NIN), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Royal Netherlands Academy of Arts and Sciences (KNAW), University of California [Davis] (UC Davis), University of California |
| Rok vydání: | 2015 |
| Předmět: |
Untranslated region
Eye Movements [SDV]Life Sciences [q-bio] Intranuclear Inclusion Bodies Gene Expression Neurodegenerative Medical and Health Sciences Transgenic Mice Genes Reporter Tremor 2.1 Biological and endogenous factors Aetiology ComputingMilieux_MISCELLANEOUS Genetics (clinical) Genetics & Heredity Genetics Parkinsonism Brain General Medicine Articles Biological Sciences Phenotype 3. Good health Protein Transport Neurological Intention tremor medicine.symptom Protein Binding Genetically modified mouse Ataxia Intellectual and Developmental Disabilities (IDD) Mice Transgenic Neuropathology Biology Rare Diseases medicine Animals Humans Reporter Molecular Biology Animal Ubiquitin Neurosciences RNA medicine.disease Brain Disorders Disease Models Animal Genes Fragile X Syndrome Disease Models Cancer research Peptides Trinucleotide Repeat Expansion |
| Zdroj: | Human Molecular Genetics, 24(17), 4948-4957. Oxford University Press Human Molecular Genetics, 24(17), 4948-57. Oxford University Press Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2015, 24 (17), pp.4948-4957. ⟨10.1093/hmg/ddv216⟩ Human molecular genetics, vol 24, iss 17 |
| ISSN: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/ddv216⟩ |
| Popis: | 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, parkinsonism and 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. |
| Databáze: | OpenAIRE |
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