The C291R Tau Variant Forms Different Types of Protofibrils

• Published in: Frontiers in molecular neuroscience 2020-03, Vol.13, p.39-39
• Main Authors: Karikari, Thomas K, Thomas, Rachel, Moffat, Kevin G
• Format: Article
• Language: English
• Subjects: aggregation; alpha-synuclein; Amino acids; Amyloidogenesis; annular protofibril; Atomic force microscopy; Circular dichroism; corticobasal degeneration; disease; Electron microscopy; expression; fibrillization; granular oligomer; Heparin; identification; linear protofibril; MAPT mutations; Monomers; Mutagenesis; Mutation; mutations; Neurodegenerative diseases; Neuroscience; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; paired helical filament; Phenotypes; Protein expression; protein-tau; Proteins; repeat domain; Spectrum analysis; tau C291R; Tau protein; transmission electron microscopy
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2020.00039

Mutations in the gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in native-state and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at ~210 nm compared with ~199 nm for tau-K18 WT. These data suggest mutation-enhanced β-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve β-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures.