Proteins with expanded glutamine repeats (polyQ) are associated with several fatal neurodegenerative diseases, including Huntington's disease. The polyQ expansion leads to the protein becoming abnormally folded, prone to aggregation and, consequently, cytotoxic. A report in Science reveals that polyQ aggregates exert their cytotoxic effect by disrupting the carefully balanced cellular homeostasis of protein folding and clearance.

Various mechanisms have been proposed to explain the cytotoxic effects of polyQ aggregates. These include the disruption of cellular processes such as transcription, energy metabolism and protein folding, and the activation of apoptosis. These varied proposals led Richard Morimoto's team at Northwestern University, Illinois, USA, to ask whether there might be a single general mechanism responsible for triggering the molecular pathology of the polyQ diseases. Specifically, they focused on whether expression of an aggregation-prone polyQ protein could affect the folding stability of normal cellular metastable proteins — proteins with a tendency towards instability.

Temperature-sensitive mutant proteins provide a useful genetic model of such metastable variants. At permissive temperatures they convey no abnormal phenotype, but at raised, restrictive temperatures the metastable balance is tilted, and the proteins misfold and fail to function. The group used various temperature-sensitive Caenorhabditis elegans strains and crossed them with transgenic lines expressing polyQ proteins. Normally, temperature-sensitive strains show their defective phenotype only at restrictive temperatures. However, when crossed with the polyQ worms the defective phenotype became apparent even at permissive temperatures.

So how were the polyQ proteins prompting the metastable proteins to misfold? Closer examination of one particular temperature-sensitive strain revealed that the abnormal crystalline structures usually formed by the misfolded protein at restrictive temperatures were also being formed in the temperature-sensitive/polyQ worms. This suggested that the polyQ protein did not exert its effect through specific interactions or aggregations with the metastable protein itself, but rather put stress on the general cellular protein folding machinery. With this in mind, the team supposed that the level of aggregation of the polyQ protein would also be increased (by positive feedback) in the temperature-sensitive/polyQ worms — and it was.

From this work the authors suggest a model whereby under normal conditions misfolding of metastable cellular proteins is adequately dealt with by the protein folding and clearance machinery. However, the expression of aggregation-prone polyQ proteins overwhelms the machinery and disrupts the homeostatic balance. It interferes with the folding environment of the cell, which, in turn, leads to the gradual accumulation of misfolded proteins, and to disease. Therefore, therapies that target this folding problem might hold promise for future polyQ disease treatment.