Species-Dependent Differences in Fibril Morphology and the Effects on Basal Forebrain Neurons of a Prion Protein Fragment (Residues 127-147)

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Prion protein mis-folding is central to the transmission and pathobiology of transmissible spongiform encephalopathies. Unfortunately, the heterogeneous and aggregation-prone nature of the disease-associated mis-folded prion protein has complicated its study. Fragments of the prion protein, such as residues 106-126 and 127-147, exhibit amyloid-like fibril formation and neurotoxicity in cell culture. These prion protein fragments serve as simplified models for the study of the mis-folded prion protein and its role in disease. We have characterized a fibril-forming peptide (residues 127-147) from elk, hamster and bovine prion proteins. At neutral pH, the elk and hamster prion peptides form distinct fibril morphologies. The hamster fibrils are ∼20 nm in width, Thioflavin T-negative, and generally lack a repetitive helical structure. The elk fibrils are thinner (∼15 nm in width), Thioflavin T-positive, and have a repetitive helical structure. Notably, the elk fibrils appear more homogeneous in their morphology and helical periodicity, whereas the hamster fibrils appear more heterogeneous and non-periodic. As observed for the elk peptide, the bovine fibrils appear homogeneous in their morphology and periodicity. Three-dimensional reconstructions from negative-stain transmission electron microscopy images of representative elk, hamster, and bovine fibrils highlight their distinct morphologies. Interestingly, the elk prion peptide, but not the hamster peptide, significantly decreased whole cell currents in rat basal forebrain neurons, similar to previous studies of a human prion peptide (residues 106-126; Alier et al., Journal of Neuroscience Research, 2010).