Abstract
In the last seven years, cryo-EM maps of neuropathological fibrils from Alzheimer's disease and other neurodegenerations have been released by various authors(1-44). The first publication(11) noted an unknown component coordinating with lysine residues in the protein, a finding recapitulated in many succeeding studies. Previous authors have emphasized difficulties in analysing this component(12,20,28,33,43,45), but current findings, using powerful visualisation software UCSF ChimeraX(46) on all publicly available maps(1-44), indicate that the issue is tractable. Lysine-coordinating extra densities have common features, including a Y-shaped substructure, suggestive of a molecular factor in common, in neuropathological fibrils from a wide range of neurodegenerations and involving misfolded proteins beta-amyloid(10,35), alpha-synuclein(27,37,39,41), prion protein(17), tau(1,5,7,8,11,12,15,16,19,22-26,29-33,35,43) and transmembrane protein 106B(5,9,18,20,24,28,36,44). A similar component, albeit in non-lysine environments, was found in neuropathological fibrils involving TAR DNA-binding protein 43(2,3) and TATA-binding protein-associated factor 15(36). The results suggest the existence of a common molecular factor, a predominantly anionic polymer, linking these diseases and raising the possibility of a unitary basis for Alzheimer's and other neurodegenerations. Based on evidence here, RNA is a feasible candidate for this putative common factor. Such findings raise the possibility of new diagnostic tests and treatments for these devastating diseases in the future.