The multiple molecular facets of fragile X-associated tremor/ataxia syndrome.

Chantal Sellier,Veronica J Peschansky,Flora Tassone,Karen Usdin,Chiara Pastori,Nicolas Charlet-Berguerand

doi:10.1186/1866-1955-6-23

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset inherited neurodegenerative disorder characterized by intentional tremor, gait ataxia, autonomic dysfunction, and cognitive decline. FXTAS is caused by the presence of a long CGG repeat tract in the 5′ UTR of the FMR1 gene. In contrast to Fragile X syndrome, in which the FMR1 gene harbors over 200 CGG repeats but is transcriptionally silent, the clinical features of FXTAS arise from a toxic gain of function of the elevated levels of FMR1 transcript containing the long CGG tract. However, how this RNA leads to neuronal cell dysfunction is unknown. Here, we discuss the latest advances in the current understanding of the possible molecular basis of FXTAS.

Highlights

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects older adults who have a large CGG-repeat tract in the 5′-untranslated region (UTR) of the Fragile X Mental Retardation 1 (FMR1) gene [1]
Whether overexpression of hnRNP A2/B1, P68/DDX5, DROSHA-DGCR8, or CUGBP1 rescues any phenotype in mouse models expressing expanded CGG repeats, would be necessary to determine the importance of these candidate proteins to FXTAS pathology
The restriction of FXTAS clinical features to unmethylated, transcriptionally active alleles with large CGG repeat numbers suggests that the expression of a mutant RNA is pathogenic to neuronal cells [55]

Summary

Introduction

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects older adults who have a large CGG-repeat tract in the 5′-untranslated region (UTR) of the Fragile X Mental Retardation 1 (FMR1) gene [1]. The crucial observation that RNAs containing expanded CGG repeats accumulate in nuclear RNA aggregates in brain sections of patients with FXTAS [50] supports the notion that elevated levels of FMR1 mRNA trigger neuronal toxicity In support of this hypothesis, heterologous expression of 90 CGG repeats in Drosophila melanogaster was shown to cause neurodegeneration and formation of ubiquitin inclusions [18]. Whether overexpression of hnRNP A2/B1, P68/DDX5, DROSHA-DGCR8, or CUGBP1 rescues any phenotype in mouse models expressing expanded CGG repeats, would be necessary to determine the importance of these candidate proteins to FXTAS pathology These caveats aside, the observations described above suggest that CGG repeats could be pathogenic by sequestering specific RNA binding proteins, resulting in loss of their normal functions, and lead to neuronal cell dysfunction (Figure 2) [56,58,61,67,68]. Much work remains to fully understand the relevance of these transcripts to the pathology observed in premutation carriers

Conclusion

Findings

41. Mirkin SM