Cryo-EM evidence for a common factor in Alzheimer's and other neurodegenerations

Abstract

In the last seven years, cryo-EM maps of neuropathological fibrils from Alzheimers disease and other neurodegenerations have been released by various authors1-44. The first publication11 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 component12,20,28,33,43,45, but current findings, using powerful visualisation software UCSF ChimeraX46 on all publicly available maps1-44, 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-amyloid10,35, alpha-synuclein27,37,39,41, prion protein17, tau1,5,7,8,11,12,15,16,19,22-26,29-33,35,43 and transmembrane protein 106B5,9,18,20,24,28,36,44. A similar component, albeit in non-lysine environments, was found in neuropathological fibrils involving TAR DNA-binding protein 432,3 and TATA-binding protein-associated factor 1536. 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 Alzheimers 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.