Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions.
The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55–200 CGG repeats) in the fragile X mental retardation 1 ( FMR1) gene.
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