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The C291R Tau Varia...
The C291R Tau Variant Forms Different Types of Protofibrils
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- Karikari, Thomas (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Thomas, R. (författare)
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Moffat, K. G. (författare)
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(creator_code:org_t)
- 2020-03-18
- 2020
- Engelska.
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 13
- Relaterad länk:
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https://www.frontier...
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visa fler...
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https://gup.ub.gu.se...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- 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
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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