RNA as a component of fibrils from Alzheimer’s disease and other neurodegenerations

Abstract

Fibrils from brains of patients with Alzheimer’s disease1–5, Parkinson’s disease6, amyotrophic lateral sclerosis7and other neurodegenerations3,4,8–18contain unknown molecules. Extra densities (EDs), containing these unknown molecules, are available to examine in electron cryo-microscopy maps from the Electron Microscopy Data Bank19, a public repository. EDs can be visualised in their protein environments using matched atomic models from the Protein Data Bank20, another public repository. Lysine-coordinating EDs from a wide range of neurodegenerative diseases1–6,8–18and EDs from the glycine-rich region of TAR DNA-binding protein 43 (TDP-43) fibrils in amyotrophic lateral sclerosis with frontotemporal lobar degeneration (ALS-FTLD)7were the subject of the present study. EDs ran parallel to the fibril axis and at right angles to protein with a repeat distance matching that of protein. They formed connections with protein consistent with a role in the guided assembly of fibrils. They had a connectivity pattern and estimated molecular weights consistent with ribonucleic acid (RNA). A straight form of RNA (ortho-RNA, oRNA) was modelled into one ED. It fitted other EDs and formed a rich symmetrical network of hydrogen bonds when docked to protein, implicating RNA as a unifying and organising factor in neurodegeneration. A new hypothesis of neurodegeneration (ponc,proteinortho-nucleic acidcomplex, pronounced ponk) is proposed in which RNA is the driver of these diseases. According to the ponc hypothesis, a particular RNA sequence (likely repetitive) enciphers a particular strain of ponc agent with its own protein fold and type of neurodegeneration. Ponc provides an explanation of fibril growth and replication, species barrier and adaptation, inherited neurodegeneration, resistance to chemicals and irradiation, protein-free transmission and co-pathologies. Ponc may also be relevant to other chronic diseases and origins of life. New treatments might be possible, targeting the unique chemical and physical properties of ponc.