page 411 by Nasrallah et al. Alanine expansions are found in several transcription factors that are associated with multiple disorders; thus, these maladies may all be rooted in inclusion body formation.
One alanine repeat–associated disorder, which causes neurological defects in infants, is caused by mutations in the ARX transcription factor. The new results show that 50% expansion of one of ARX's alanine stretches leads to inclusion body formation in neurons. As with glutamine repeat–induced inclusions, the insoluble clumps of mutant ARX are tagged with ubiquitin, as though the cell is trying, yet failing, to degrade the misfolded proteins. Overexpressed Hsp70 chaperone cleared the inclusions.
In cell culture, expression of the mutant ARX increased cell death. Arrasate et al. (Nature. 431:805–810) recently reported that inclusion body formation was an effective coping mechanism by which polyglutamine-expanded proteins are kept from doing harm. But ARX inclusions may cause extra problems by removing both ARX and its interacting partners from the functional pool, thus disrupting transcription, altering cell physiology, and causing cell death. To confirm this theory, the authors plan to identify ARX's gene targets and examine their expression levels in normal and inclusion-containing cells.