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Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS
- Source :
- 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
- Publication Year :
- 2015
-
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, 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 09646906 and 14602083
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....e37c0e3e100d03494d8cb8dfa523b8ec