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The C291R Tau Variant Forms Different Types of Protofibrils

Artikel i vetenskaplig tidskrift
Författare Thomas Karikari
R. Thomas
K. G. Moffat
Publicerad i Frontiers in Molecular Neuroscience
Volym 13
Sidor 9
ISSN 1662-5099
Publiceringsår 2020
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 9
Språk en
Länkar dx.doi.org/10.3389/fnmol.2020.00039
Ämnesord MAPT mutations, tau C291R, corticobasal degeneration, granular oligomer, annular protofibril, linear protofibril, atomic force microscopy, transmission electron microscopy, paired helical filament, protein-tau, alpha-synuclein, repeat domain, aggregation, expression, mutations, disease, fibrillization, identification, Neurosciences & Neurology
Ämneskategorier Neurovetenskaper

Sammanfattning

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 similar to 210 nm compared with similar to 199 nm for tau-K18 WT. These data suggest mutation-enhanced beta-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 beta-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures.

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