The C291R Tau Variant Forms Different Types of Protofibrils
Open Access
- 18 March 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Molecular Neuroscience
- Vol. 13, 39
- https://doi.org/10.3389/fnmol.2020.00039
Abstract
Mutations in the MAPT 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 MAPT 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.Keywords
Funding Information
- Biotechnology and Biological Sciences Research Council
This publication has 45 references indexed in Scilit:
- The microtubule-associated tau protein has intrinsic acetyltransferase activityNature Structural & Molecular Biology, 2013
- Tau Protein Assembles into Isoform- and Disulfide-dependent Polymorphic Fibrils with Distinct Structural PropertiesOnline Journal of Public Health Informatics, 2011
- Annular Protofibrils Are a Structurally and Functionally Distinct Type of Amyloid OligomerOnline Journal of Public Health Informatics, 2009
- Tau exon 10 alternative splicing and tauopathiesMolecular Neurodegeneration, 2008
- Mutations causing neurodegenerative tauopathiesBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2005
- Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseasesBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2005
- Mixtures of Wild-type and a Pathogenic (E22G) Form of Aβ40 in Vitro Accumulate Protofibrils, Including Amyloid PoresJournal of Molecular Biology, 2003
- Annular α-Synuclein Protofibrils Are Produced When Spherical Protofibrils Are Incubated in Solution or Bound to Brain-Derived MembranesBiochemistry, 2002
- Role of Cysteine-291 and Cysteine-322 in the Polymerization of Human Tau into Alzheimer-like FilamentsBiochemical and Biophysical Research Communications, 2001
- Structure, Microtubule Interactions, and Paired Helical Filament Aggregation by Tau Mutants of Frontotemporal DementiasBiochemistry, 2000