Fragile X-associated tremor/ataxia syndrome (
FXTAS) is a
neurodegenerative disorder caused by a CGG-repeat expansion in the
5' UTR of the FMR1 gene on the X-chromosome. Both elevated levels of the expanded FMR1
mRNA and aberrant expression of a
polyglycine protein (FMRpolyG) from the CGG-repeat region are hypothesized to trigger the pathogenesis of
FXTAS. While increased expression of FMRpolyG leads to higher toxicity in
FXTAS models, the pathogenic effect of this
protein has only been studied in the presence of CGG-containing
mRNA. Here we present a model that allows measurement of the effect of FMRpolyG-expression without co-expression of the corresponding CGG
mRNA hairpin. This allows direct comparison of the effect of the FMRpolyG
protein per se, vs. that of the FMRpolyG
protein together with the CGG
mRNA hairpin. Our results show that expression of the FMRpolyG, in the absence of any CGG
mRNA, is sufficient to cause reduced cell viability,
lamin ring disruption and aggregate formation. Furthermore, we found FMRpolyG to be a long-lived
protein degraded primarily by the
ubiquitin-
proteasome-system. Together, our data indicate that accumulation of FMRpolyG
protein per se may play a major role in the development of
FXTAS.