Cells have evolved multiple mechanisms to ensure proper folding, but a number of molecular and biophysical events - such as changes in pH or temperature, mutations, and oxidation - can disrupt a protein's native shape.
When polypeptides fail to achieve or maintain their proper conformation, they commonly aggregate into abnormal “amyloid fibril” structures. Amyloid fibrils define a diverse group of degenerative conditions, including amyotrophic lateral sclerosis, prion diseases, and Alzheimer and Parkinson diseases. In Alzheimer disease, the amyloid fibrils are deposited extracellularly; however, in Parkinson and Huntington disease, similar amyloid fibrils accumulate in the cytoplasm and nucleus of the cell respectively. How amyloid formation promotes disease has generated considerable debate, though mounting evidence implicates the early protofibrillar aggregates as the toxic species.
In a new study in the open-access journal PLoS Biology, Leila Luheshi et al. worked with the fruit fly Drosophila to identify the intrinsic determinants of amyloid ß (Aß) pathogenicity in an animal model of Alzheimer disease. (Aß peptide is a primary component of amyloid plaques in the brains of patients with Alzheimer disease.) Determining how amyloid formation causes disease requires a better understanding of the molecular and biophysical conditions that promote protein aggregation. But such an understanding has proven technically challenging, in part because protein misfolding and aggregation in test tubes can't replicate cellular pathways designed to mitigate the toxic effects of these events. Luheshi et al. circumvented this problem by integrating computational predictions of protein aggregation propensities with in vitro experiments to test the predictions and in vivo mutagenesis experiments to link predicted aggregation propensity with observed neurodegeneration in the flies.