title: Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS.
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.
authors.affiliation: Department of Clinical Genetics, r.hukema@erasmusmc.nl.
authors.forename: Renate K
authors.initials: RK
authors.lastname: Hukema
authors.affiliation: Department of Clinical Genetics.
authors.forename: Ronald A M
authors.initials: RA
authors.lastname: Buijsen
authors.affiliation: Department of Neuroscience.
authors.forename: Martijn
authors.initials: M
authors.lastname: Schonewille
authors.affiliation: Department of Biochemistry and Molecular Medicine and.
authors.forename: Chris
authors.initials: C
authors.lastname: Raske
authors.affiliation: Department of Clinical Genetics.
authors.forename: Lies-Anne W F M
authors.initials: LA
authors.lastname: Severijnen
authors.affiliation: Department of Clinical Genetics.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Nieuwenhuizen-Bakker
authors.affiliation: Department of Clinical Genetics.
authors.forename: Rob F M
authors.initials: RF
authors.lastname: Verhagen
authors.affiliation: Department of Clinical Genetics.
authors.forename: Lisanne
authors.initials: L
authors.lastname: van Dessel
authors.affiliation: Department of Cell Biology, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.affiliation: IGBMC, 67404 Illkirch, France and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.affiliation: Department of Neuroscience The Netherlands Institute for Neuroscience, Amsterdam 1105 BA, The Netherlands.
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.affiliation: Department of Biochemistry and Molecular Medicine and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.affiliation: Department of Neurological Surgery, School of Medicine, University of California Davis, CA 95618, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.affiliation: Department of Clinical Genetics.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005133:Eye Movements / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology*; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D014202:Tremor / Q000235:genetics* / Q000503:physiopathology*; D019680:Trinucleotide Repeat Expansion; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D010455:Peptides; D025801:Ubiquitin; C011080:polyglycine