15 March 2008. Amidst the debate around whether pathogenic mutations of presenilin harm cells by a gain of toxic function, or a loss of essential normal function (see ARF related news story), new results with another disease-causing protein suggest that in some cases the answer may be not one or the other, but both. In a report in the March 12 issue of Nature, Huda Zoghbi and colleagues at Baylor College of Medicine in Houston, Texas, provide evidence that the same polyglutamine expansion mutation in ataxin, the cause of spinocerebellar ataxia-1, can lead to simultaneous gain and loss of function depending on which cellular proteins ataxin partners with.
First author Janghoo Lim and coworkers show that in cells, ataxin participates in at least two large native protein complexes. On the one hand, polyglutamine expansion and phosphorylation, two features required for pathogenesis, promote the formation of complexes with a newly identified partner, RBM17. These complexes play a role in neurodegeneration, in an apparent gain of function. At the same time, there is less ataxin available for a physiological interaction with capicua (see ARF related news story), creating a partial loss of function.
Evidence that a loss of function contributes to disease in conjunction with a dominant gain-of-function effect comes from mice, where animals expressing solely polyglutamine-expanded ataxin have a worse disease phenotype than animals that also carry a (presumably protective) wild-type allele.
“Our finding that the interactions of the mutant protein with its usual partners are differentially affected by the poly-glutamine expansion offers a mechanistic explanation for how mutant proteins can gain and lose function simultaneously,” the authors write.—Pat McCaffrey.
Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, Orr HT, Zoghbi HY. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature. 2008 Mar 12; [Epub ahead of print] Abstract