Summary Polyglutamine-repeat diseases are neurodegenerative ailments elicited by glutamine-encoding CAG nucleotide expansions within endogenous human genes. Despite efforts to understand the basis of these diseases, the precise mechanism of cell death remains stubbornly unclear. Much of the data seems consistent with a model in which toxicity is an inherent property of the polyglutamine repeat, whereas host protein sequences surrounding the polyQ expansion modulate severity, age of onset, and cell specificity. Recently, a gene, pqn-41encoding a glutamine-rich protein was found to promote normally-occurring non-apoptotic cell death in C. elegans. Here we review evidence for toxic and modulatory roles for polyQ repeats and their host proteins, respectively, and suggest similarities with pqn-41 function. We explore the hypothesis that toxicity mediated by glutamine-rich motifs may be important not only in pathology, but also in normal development.

Programmed cell death is a ubiquitous process in metazoan development. Apoptosis, one cell death form, has been studied extensively. However, mutations inactivating key mammalian apoptosis regulators do not block most developmental cell culling, suggesting that other cell death pathways are likely important. Recent work in the nematode Caenorhabditis elegans identified a non-apoptotic cell death form mediating the demise of the male-specific linker cell. This cell death process (LCD, linker cell-type death) is morphologically conserved, and its molecular effectors also mediate axon degeneration in mammals and Drosophila. To develop reagents to manipulate LCD, we established a simple high-throughput screening protocol for interrogating the effects of small molecules on C. elegans linker cell death in vivo. From 23,797 compounds assayed, 11 reproducibly block linker cell death onset. Of these, five induce animal lethality, and six promote a reversible developmental delay. These results provide proof-of principle validation of our screening protocol, demonstrate that developmental progression is required for linker cell death, and suggest that larger scale screens may identify LCD-specific small-molecule regulators that target the LCD execution machinery.