Single amino-acid substitutions in the prion protein have been found to lead to resistance or susceptibility to amyloid fibril formation. In humans, the presence of methionine at position 129 in the prion protein results in increased susceptibility to prion disease, while the presence of valine at that position appears to be protective. It is hypothesized that the codon for M129 is an alternative initiation site for translation, which results in a truncated molecule that is missing the first 128 amino acids, including the signal peptide. This N-terminal truncated form of the prion molecule will not be transported to the extracellular space and thus will accumulate in the cytosol where it is more susceptible to fibril formation and aggregation; this aggregation could hinder normal degradation processes and cause disease. The results of experimental studies on truncated prion molecules support this hypothesis. To test the hypothesis, a gene segment, which when transcribed would result in a prion molecule starting at methionine 129, could be introduced into a convenient experimental animal to see if there is increased incidence of prion disease. Or, fibrils from the brains of affected M129/M129 homozygous individuals could be isolated and the molecules in the fibrils analyzed to determine the identity of the N-terminal amino acid(s). We predict that those isolates will have a preponderance of molecules that start with the methionine at position 129 in the intact protein.