PerspectiveDevelopment

Cell Death by Glutamine Repeats?

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Science  24 Feb 2012:
Vol. 335, Issue 6071, pp. 926-927
DOI: 10.1126/science.1219834

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Summary

A number of eukaryotic proteins contain stretches of repeating glutamine residues (1). For example, huntingtin pro- tein contains a glutamine-repeat sequence of 6 to 35 residues, and prion protein has a domain rich in glutamine and asparagine residues (Q/N-rich domain). Expansion of the glutamine repeat in huntingtin and at least seven other proteins results in neurodegenerative disease (2), whereas conformational changes in prion protein cause a range of spongiform encephalopathies (3). Glutamine repeats and Q/N-rich domains can form α-helical and coiled-coil secondary structures, driving protein aggregation. Aggregation of numerous disease-associated proteins that do not contain polyglutamine domains has been associated with neurodegeneration (such as the β-amyloid peptide and the tau protein in Alzheimer's disease). Thus, the presence of glutamine-rich domains in proteins associated with neurodegeneration could be due to their ability to induce protein aggregation per se. Alternatively, glutaminerich proteins could have a “natural role” in inducing cell death that becomes dysregulated in neurodegenerative disease. On page 970 of this issue, Blum et al. (4) identify a Q/N-rich protein that aids in the programmed cell death of a specific cell in the model nematode Caenorhabditis elegans. This result provides support for the “natural role” explanation for the association of glutamine-rich proteins and neurodegeneration.