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FXTAS

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an X-linked inherited, late onset neurodegenerative disorder resulting in tremor, ataxia, brain atrophy, cognitive loss, dementia, and early death in some individuals. The disorder is caused by an expansion of 55-200 CGG repeats in the 5’-UTR of the FMR1 gene, also referred to as premutation (PM).


The prevalence of PM carriers in the general population is relatively high, with an estimation of about 1 in 855 males and 1 in 291 females. This results in about 20 Million PM carriers worldwide. The chances of developing FXTAS increase dramatically with age, with approximately 45.5% of male and 16.5% of female PM carriers over the age of 50 affected. Altogether, 1 in 3000 men in the general population over 50 are at risk of developing FXTAS. For females these numbers are much lower due to the presence of a second non-affected X chromosome. To date, no treatment exists for this devastating disease.


The major hallmark in FXTAS neuropathology is the presence of ubiquitin-positive intranuclear inclusions in both neurons and astrocytes that also contain the mutant FMR1 mRNA. A striking characteristic is that PM carriers with and without FXTAS show 2-8 fold elevated FMR1 mRNA levels in leucocytes and 2-3 fold in brain tissue with paradoxically slightly reduced FMRP protein levels. These observations have led to the hypothesis that FXTAS results from a toxic “RNA gain-of-function” mechanism, in which mutant RNA with the expanded CGG repeats is pathogenic by sequestration of RNA binding proteins within nuclear aggregates.

 
Recently, an additional mechanism of toxicity, that is triggered by repeat associated non-AUG initiated (RAN) translation, has been proposed to underlie the pathology in FXTAS. This is based on evidence that nucleotide repeats can be translated into protein even if they do not reside in a coding region of a gene. In case of FXTAS it is proposed that RAN translation initiated in the 5’-UTR of FMR1 mRNA results in the production of a cytotoxic polyGlycine (FMRpolyG) containing protein. Indeed, our group could confirm the presence of FMRpolyG in bthe characteristic inclusions in post-mortem material from a patient with FXTAS. Although the exact underlying mechanisms of RAN translation are unknown, it seems to contribute to the toxic “gain-of-function” mechanism in FXTAS.

 
A major part of the current knowledge concerning the molecular mechanism underlying FXTAS comes from work with our animal models. Our expanded CGG knock-in (exCGG-KI) mice have allowed us to model the pathophysiology of FXTAS. In addition, we have developed an inducible mouse model. With this model, we have demonstrated that the expanded CGG repeat and not overexpression of a CGG RNA per se is toxic in vivo. This mouse model allows us to turn on expression of mutant CGG RNA and study disease progress, and subsequently turn it off to study if further disease development is halted or even reversed. Interestingly, stopping expression of the mutant CGG RNA resulted in the reduction of the number and size of ubiquitin- and FMRpolyG-positive inclusions. Most importantly, this reversibility was confirmed with a behavioral test as functional read-out.

 
The overall aim of our research is to further understand the molecular processes involved in disease pathology and to use this knowledge to develop strategies to intervene in these processes. Our group has several state-of-the-art in vitro and in vivo models to study FXTAS at its disposal. Together with our (international) collaborators we use these models in our quest for a targeted therapeutic intervention for FXTAS.

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Current hypothesis for the molecular mechanism underlying FXTAS
. The CGG repeat in the FMR1 RNA could potentially lead to 3 threats: Toxicity of the free CGG containing mRNA (1). The CGG repeat in the RNA forms a hairpin structure that binds several (RNA binding) proteins. This in turn leads to sequestration of several other proteins and thus the formation of inclusions and depletion of the proteins and their normal function (2). The hairpin structure in the mutant CGG RNA stalls the scanning ribosome that results in the usage of an alternative non-AUG startsite and the synthesis of a polyGlycin protein that can cause toxicity (3), or the polyGlycin protein can also aggregate in the inclusions and thus contribute to the sequestration model (2). Not only the individual threats could be the potential cause of disease, but it is likely that a combination of these threats is involved in disease pathogenesis.

 

Links

National Fragile X Foundation-FXTAS page

Dutch Fragile X Foundation-FXTAS page