The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome

Abstract

Recent studies have reported that alleles in the premutation range in the FMR1 gene in males result in increased FMR1 mRNA levels and at the same time mildly reduced FMR1 protein levels. Some elderly males with premutations exhibit an unique neurodegenerative syndrome characterized by progressive intention tremor and ataxia. We describe neurohistological, biochemical and molecular studies of the brains of mice with an expanded CGG repeat and report elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 and the 20S catalytic core complex of the proteasome as constituents. An increase was observed of both the number and the size of the inclusions during the course of life, which correlates with the progressive character of the cerebellar tremor/ataxia syndrome in humans. The observations in expanded-repeat mice support a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggest a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. This mouse model will facilitate the possibilities to perform studies at the molecular level from onset of symptoms until the final stage of the disease.

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

“…In 25-week old CGG mice also inclusions in the amygdala were observed. Interestingly, no inclusions have been observed in other brain regions at this age, including amygdala (Willemsen et al, 2003). It seems that inclusions start to develop around this time point, with the pituitary gland and amygdala being the first sites of inclusion development followed by other regions in the brain at 40-50 weeks of age (Willemsen et al, 2003).…”

“…The CGG-repeat in the mouse model shows instability upon transmission to the next generation (Brouwer et al, 2007), similar to humans. Also, the CGG mice show elevated Fmr1 mRNA levels (Brouwer et al, 2007), as well as ubiquitin-positive neuronal inclusions throughout the brain (Bontekoe et al, 2001;Willemsen et al, 2003). Aberrant behavior in mice was described by Van Dam and colleagues, including mild learning deficits and increased anxiety (Van Dam et al, 2005).…”

“…An expanded CGG-repeat knock-in (CGG) mouse model has been generated (Bontekoe et al, 2001;Willemsen et al, 2003), by substituting the endogenous mouse (CGG) 8 with a human (CGG) 98 . The CGG-repeat in the mouse model shows instability upon transmission to the next generation (Brouwer et al, 2007), similar to humans.…”

The cyclic AMP phenotype of fragile X and autism

“…Knock-in mice with an expansion of CGG repeats in the FMR1 promoter have been developed to understand the human FX premutation and its expansion. Mice engineered using a yeast artificial chromosome (YAC) with a (CGG) 98 human premutation (Bontekoe, Bakker et al 2001;Willemsen, Hoogeveen-Westerveld et al 2003) have several features in common with the human FX premutation tremor-ataxia phenotype (Greco, Hagerman et al 2002). An FX knock-in premutation mouse engineered using serial ligation (SL) methodology (Grabczyk and Usdin 1999), rather than with a YAC, has reduced FMRP expression that is associated with repeat length and varies in its extent across the brain.…”

Molecular Insights into Mental Retardation: Multiple Functions for the Fragile X Mental Retardation Protein?

“…The origin of this inclusion is unknown, although elevated FMR1 mRNA levels in these premutation carriers may lead to the neuropathological changes (Greco et al, 2002). Interestingly, engineered mice with premutation alleles also show elevated FMR1 mRNA levels and ubiquitin-positive intranuclear inclusions in neuronal and glial cells (Willemsen et al, 2003).…”