Advances in understanding the molecular basis of FXTAS

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as other forms of clinical involvement in carriers without FXTAS, are thought to arise from a toxic gain of function of transcriptionally active FMR1 containing expanded CGG repeats. Although the precise mechanisms involved in rCGG toxicity are unknown, here we discuss the latest advances and models that contribute to the understanding of the molecular basis of FXTAS, and the emerging view of FXTAS as the end-stage of a process that begins in early development.

Figure 1.

Images of intranuclear inclusions in mouse and human CNS tissues. (Left panel) Image of a Bergmann glial cell (mouse) located just beneath the Purkinje cell layer; inclusion (red; anti-ubiquitin IHC staining) in glial cell body (green; anti-gfap) in granule layer (heavy blue DAPI staining of granule cell nuclei); radial glial cell processes extend from the granule–Purkinje cell interface into the molecular layer (toward upper left). Scale bar, 10 µm. One hundred sixty-two CGG mouse; 70 week. (Lower right panel) Enlargement of the boxed portion of the image at left. (Upper right panel) Cortical cell neurons in human post-mortem tissue, stained with anti-ubiquitin Ab. Note distinct nucleolus in cell at left. Mouse and human images courtesy of Drs Jurgen Wenzel and Claudia Greco, respectively.

Figure 2.

Models of transcription-dependent toxicity in FXTAS. RNA toxicity can be direct, as in sequestration of proteins from other functions in the cell (e.g. DM model) and/or activation of proteins upon binding to RNA, which then signal downstream events. RNA involvement may also be indirect, as part of a co-transcriptional mechanism. For example, it is possible that the expanded CGG repeat promotes the formation of R-loops which in turn lead to DNA damage (e.g. of the displaced strand) and a consequent DNA damage response involving γH2AX and other DDR proteins (90).