Fragile X-associated tremor/ataxia syndrome

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some but not all carriers of small, noncoding CGG-repeat expansions (55-200 repeats; premutation) within the fragile X gene (FMR1). Principal features of FXTAS include intention tremor, cerebellar ataxia, Parkinsonism, memory and executive function deficits, autonomic dysfunction, brain atrophy with white matter disease, and cognitive decline. Although FXTAS was originally considered to be confined to the premutation range, rare individuals with a gray zone (45-54 repeats) or an unmethylated full mutation (>200 repeats) allele have now been described, the constant feature of the disorder remaining the requirement for FMR1 expression, in contradistinction to the gene silencing mechanism of fragile X syndrome. Although transcriptional activity is required for FXTAS pathogenesis, the specific trigger(s) for FXTAS pathogenesis remains elusive, highlighting the need for more research in this area. This need is underscored by recent neuroimaging findings of changes in the central nervous system that consistently appear well before the onset of clinical symptoms, thus creating an opportunity to delay or prevent the appearance of FXTAS.

Keywords: CGG repeat; FXTAS; RNA toxicity; dementia; neurodegeneration; premutation.

Figure 1

Models for pathogenesis of FXTAS; all are based the requirement for expression of the expanded (premutation) FMR1 mRNA. Post-transcriptional models are based on the properties of the expanded CGG-repeat region within the free mRNA. The CGG-repeat element, likely through its ability to form higher-order structure (e.g., hairpin; depicted in yellow), has been demonstrated to sequester one or more proteins (green spheres), rendering the cell functionally deficient in those proteins; the exemplar for this process is the muscleblind-like 1 protein of myotonic dystrophy. An alternative mechanism has been proposed in which the CGG element leads to aberrant initiation of translation, out of phase with the FMRP coding sequence, and at non-AUG codons. In this model, the short peptides are proposed to be toxic. Despite the focus on post-transcriptional mechanisms, co-transcriptional events (e.g., R-loop formation) can also lead to cellular toxicity, in this instance through failure to clear DNA damage and its repair at/near the R-loop. Although R-loop formation and DNA damage repair (DDR) are occurring normally throughout the genome, occasional failure to clear the DDR response can lead to continued signaling and recruitment of repair proteins. In this regard, we have observed the presence of the DDR signaling protein, gH2AX, in the inclusions, as well as its induction in model systems of CGG-repeat overexpression. None of these models is mutually exclusive.