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

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.

Figure 1

Quantification of FMR1 mRNA levels in the three allele categories (normal, intermediate, and premutation) shows that FMR1 mRNA expression increases significantly with increasing CGG repeat number. The solid blue line on the plot shows a piecewise linear regression fit, with FMR1 mRNA expression increased significantly in all three groups (P = 0.012, P < 0.001, and P < 0.001 for normal, intermediate, and premutation carriers, respectively).

Figure 2

Various RNA binding proteins have been found to associate with RNAs containing expanded CGG repeats. Purα, DGCR8, and hnRNP A2/B1 bind directly to the CGG-containing RNA, whereas Rm62, SAM68, and CUGBP1 are recruited in trans through protein-protein interactions.

Figure 3

Expression of the minor splice isoform in the ASFMR1 transcript (131 bp), located near the ASFMR1 promoter. Expression of this isoform increases in premutation carriers (P < 0.001), and shows a similar trend in subjects with intermediate alleles (P = 0.0528) compared with normal alleles. The solid blue line on the plot shows a piecewise linear regression fit (fitted on the log scale then exponentiated for plotting), with separate slopes in the normal, intermediate, and premutation alleles.

Figure 4

Mechanisms that may contribute to fragile X-associated tremor/ataxia (FXTAS) pathology. Expression of FMR1 mRNA and associated antisense transcripts are increased inpremutation carriers. Some transcripts accumulate in the nucleus and recruit various RNA binding proteins, while export and non-AUG translation results in production of polyglycine-containing or polyalanine-containing proteins.