The environmental dependency of protein folding best explains prion and amyloid diseases

Understanding the second half of the genetic code, i.e., protein folding, is not only of immense importance for using the results of genome sequencing efforts, but also is required to understand how a subset of human proteins undergoes the conformational changes that render them pathogenic (1–11). The amyloid and prion diseases appear to result from the conversion of one of about 20 normally soluble and functional proteins into a β-sheet-rich quaternary structure that is often fibrilar (2, 5, 6, 9, 12–15). This conversion likely occurs in the partially denaturing environment of a cellular compartment such as a lysosome, where the lower pH (or otherwise denaturing) environment effects the conformational changes that facilitate amyloid and prion self-assembly (3, 5). This process does not challenge Christian Anfinsen’s hypothesis and demonstration that a proteins amino acid sequence is a strong determinant in specifying its fold, but it does enforce the point made by Anfinsen and by many others that the exact aqueous environment (pH, temperature, ionic strength, presence of chaotropic agents) also strongly influences the conformation adopted by the polypeptide (5). The mechanistic role that amyloid fibrils play in human amyloid disease is receiving attention from numerous groups. What is clear is that there is an overwhelming amount of evidence to support the cause and effect relationship in amyloid disease, but the amyloid hypothesis has not yet been proven (5, 10, 16–22). At the moment, it isn’t clear whether the neuropathology observed results from soluble or insoluble fibril-like assemblies operating from within the cell or from the extracellular deposits seen at autopsy. Prion diseases are even more remarkable in that the prion protein (Prp) scrapie isoform (PrP^sc) deposits in an animal or human that facilitate neurodegeneration can be transmitted …