Fragile X-associated tremor/ataxia syndrome (
FXTAS) is a rare
neurodegenerative disorder caused by a 55-200 CGG repeat expansion in the
5' untranslated region of the Fragile X
Mental Retardation 1 (FMR1) gene.
FXTAS is characterized by progressive
cerebellar ataxia,
Parkinsonism,
intention tremors and
cognitive decline. The main neuropathological hallmark of
FXTAS is the presence of
ubiquitin-positive intranuclear inclusions in neurons and astrocytes throughout the brain. The molecular pathology of
FXTAS involves the presence of 2 to 8-fold elevated levels of FMR1
mRNA, and of a repeat-associated non-AUG (RAN) translated
polyglycine peptide (FMRpolyG). Increased levels of FMR1
mRNA containing an expanded CGG repeat can result in cellular toxicity by an
RNA gain-of-function mechanism. The increased levels of CGG repeat-expanded FMR1 transcripts may create
RNA foci that sequester important cellular
proteins, including
RNA-binding proteins and FMRpolyG, in intranuclear inclusions. To date, it is unclear whether the FMRpolyG-positive intranuclear inclusions are a cause or a consequence of
FXTAS disease pathology. In this report we studied the relation between the presence of neuronal intranuclear inclusions and behavioral deficits using an inducible mouse model for
FXTAS. Neuronal intranuclear inclusions were observed 4 weeks after dox-induction. After 12 weeks, high numbers of FMRpolyG-positive intranuclear inclusions could be detected in the hippocampus and striatum, but no clear signs of behavioral deficits related to these specific brain regions were found. In conclusion, the observations in our inducible mouse model for
FXTAS suggest a lack of correlation between the presence of intranuclear FMRpolyG-positive aggregates in brain regions and specific behavioral phenotypes.