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).

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.