Fig. 7.

Diagrammatic representation of hypothesized FXTAS inclusion formation. Within FXTAS brain nuclei, proteins (yellow hexagons) destined for removal are tagged with ubiquitin and SUMO 2/3 chains, which are bound by the UPS for degradation. Polyubiquitinated and polySUMOylated proteins may form small aggregates with each other and/or RNA, at which point p62 will shuttle the aggregate out of the nucleus to an autophagosome for removal. Over time, as the FXTAS patient experiences higher levels of oxidative stress and DNA damage and decreased functioning of the UPS due to aging or injury, the levels of damaged/oxidized proteins and DNA damage mediators requiring removal increase. Paired with decreased UPS functionality, these proteins get tagged for removal but build up in the nucleus, aggregating with other proteins and RNA. p62 may attempt to shuttle the aggregate out to the autophagosome, but if the accumulation becomes too large, p62 has no way of shuttling the mass out of the nucleus in post-mitotic cells, resulting in an inclusion