One Misfolded Protein Allows Others to Sneak By

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Science  10 Mar 2006:
Vol. 311, Issue 5766, pp. 1385-1386
DOI: 10.1126/science.1125246

Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis—these neurodegenerative disorders are among many inherited diseases that have been linked to genetic mutations that result in the chronic aggregation of a single specific protein. Cellular and animal models of these disorders are consistent with misfolded conformers, oligomers, and/or aggregates of the proteins huntingtin, α-synuclein, amyloid-β peptide, and superoxide dismutase-1 as the respective toxic culprits of these late-onset degenerations. What has been puzzling about the progression of each of these diseases is the perturbation of a wide range of cellular pathways (transcription, energy metabolism, microtubule transport, synaptic function, and apoptosis, among others), and this collective dysfunction of processes has also been proposed to underlie the pathogenesis of these diseases. Could a single “aggregation-prone” protein wreak so much havoc? A report by Gidalevitz et al. on page 1471 of this issue (1) has questioned whether there might be a general mechanism by which an aggregation-prone protein can have so many cellular effects.

The mutations that cause polyglutamine (polyQ) diseases, including Huntington's disease and a number of spinocerebellar ataxias, result in the expansion of a tract of glutamine residues to a length beyond a threshold of generally 35 to 40 glutamines, rendering the protein in which the tract is harbored as pathogenic. This correlates with a dramatic increase in the rate at which the polyQ tract can self-assemble into fibrillar aggregates (2). Morimoto and colleagues have previously used the nematode Caenorhabditis elegans to model polyQ disease by expressing pathogenic and nonpathogenic polyQ peptides that are fused to yellow or green fluorescent proteins in muscle (3) and neuronal (4) cells. Fluorescent polyQ aggregates and a corresponding phenotype were observed in worms expressing pathogenic polyQ, whereas nonpathogenic peptides had no effect.

The global consequences of an aggregation-prone protein on cellular protein folding homeostasis.

(Top) Under normal physiological conditions, polymorphisms in genes can result in the expression of proteins that are mild folding variants that are correctly folded or cleared out of the cell by protein quality control mechanisms. (Bottom) In the presence of a chronic aggregation-prone protein such as those associated with neurodegenerative diseases, the protein folding and clearance process becomes overwhelmed. Proteins that are normally innocuous are no longer correctly folded, leading to dysfunction in a diverse set of cellular pathways. In turn, these structurally and functionally unrelated proteins generate a positive feedback loop and exacerbate the misfolding of the aggregation-prone protein, thereby acting as modifiers of this process.


To uncover the cellular consequences of the chronic expression of an aggregation-prone protein, Gidalevitz et al. used functionally unrelated temperature-sensitive mutations and selected the polyQ worm as a model of a protein conformation disease. Such mutations are highly dependent on their cellular environment and do not display a phenotype at a “permissive” temperature. However, when the temperature is raised to become “restrictive,” they cause disturbances in the folding of their host protein, with deleterious consequences. The phenotypes of the temperature-sensitive mutants chosen for this study are rarely observed at 15°C but are present in more than 95% of the worms at 25°C, and they include early embryonic and larval lethality, slow movement in adults, abnormal body shape, and an egg-laying defect. These temperature-sensitive strains were crossed to worms that express either polyQ40 (pathogenic) or polyQ24 (nonpathogenic) in muscle cells. The specific temperature-sensitive phenotype was exposed in worms expressing pathogenic polyQ40, but not polyQ24, at 15°C. One of these temperature-sensitive strains (UNC-15) has a mutation in the homolog of paramyosin, a muscle structural protein, which at 25°C forms paracrystalline structures that are quite distinct from aggregates of proteins with a polyQ tract. In the presence of pathogenic polyQ40, UNC-15 animals formed these paracrystalline structures at the permissive temperature. The expression of pathogenic polyQ40 thus disturbed the global balance of protein folding quality control in the muscle of these animals and exposed the phenotypes of distinct temperature-sensitive mutations at the permissive temperature. Gidalevitz et al. showed that this phenomenon extends to the expression of pathogenic polyQ in neuronal cells and that its effect on the mutant phenotype reflects specific molecular interactions within a cell type rather than an overall decrease in the fitness of the organism. Therefore, the chronic expression of polyQ40, an aggregation-prone protein, can compromise the function of many structurally and functionally unrelated proteins.

The authors further questioned whether the misfolding of a temperature-sensitive protein could in turn enhance the misfolding of the polyQ-containing protein. They found that aggregation of pathogenic polyQ40 at the permissive temperature dramatically increased when worms also harbored a temperature-sensitive mutation in genes encoding either paramyosin or the small GTP-binding protein ras. The mutations in these genes have no adverse effects under normal physiological conditions, yet they substantially enhanced the aggregation of the polyQ-containing proteins. This demonstrates that mild folding variants in proteins that are not involved in protein folding or clearance pathways can behave as modifiers of pathogenic polyQ phenotypes and toxicity.

This work indicates that the chronic expression of a misfolded protein can upset the cellular protein folding homeostasis under physiological conditions. These results have implications for pathogenic mechanisms in protein conformational diseases. The human genome harbors a load of polymorphic variants and mutations that might be prevented from exerting deleterious effects by protein folding and clearance quality control mechanisms in the cell. However, should these mechanisms become overwhelmed, as in a protein conformation disease, mild folding variants might contribute to disease pathogenesis by perturbing an increasing number of cellular pathways (see the figure). Therefore, the complexity of pathogenic mechanisms identified for protein conformation diseases could in part result from the imbalance in protein folding homeostasis. These folding-defective proteins may in turn compromise the overall folding capacity of the cell and act as genetic modifiers of disease. In the case of Huntington's disease, this may contribute to the 40% of the variance in age of onset that is not attributed to polyQ repeat length but to genes other than the HD gene (5) and to the wide variation in disease presentation between individuals with the same polyQ mutation. In a genetic screen of the worm, Nollen et al. identified close to 200 genes with diverse functions that could modify polyQ protein aggregation (6). As genetic modifiers of Huntington's disease and other protein conformation diseases are identified, it will be intriguing to test whether they too can have an impact on protein homeostasis.


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