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PMID:20193038

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Citation

Feuillette, S, Miguel, L, Frébourg, T, Campion, D and Lecourtois, M (2010) Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein. J. Neurochem. 113:895-903

Abstract

Tau is a neuronal microtubule-associated protein involved in microtubules assembly and stabilization. Tauopathies, including Alzheimer's disease and fronto-temporal dementia with parkinsonism linked to chromosome 17, are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of abnormally and hyperphosphorylated Tau. Currently, the molecular mechanisms underlying Tau-mediated cellular toxicity remain elusive. To address the determinants of Tau neurotoxicity, we used Drosophila models of human tauopathies to study the microtubule-binding properties of human Tau proteins in vivo. We showed that, in contrast to endogenous Drosophila Tau, human Tau proteins bind very poorly to microtubules in Drosophila, and are mostly recovered as soluble cytosolic hyperphosphorylated species. This weak binding of human Tau to microtubules is neither because of microtubules saturation nor competition with endogenous Drosophila Tau, but clearly depends on its phosphorylation degree. We also reported that accumulation of cytosolic hyperphosphorylated forms of human Tau proteins correlates with human Tau-mediated neurodegeneration in flies, supporting the key role of soluble cytosolic hyperphosphorylated Tau proteins as toxic species in vivo.

Links

PubMed Online version:10.1111/j.1471-4159.2010.06663.x

Keywords

Animals; Animals, Genetically Modified; Cytosol/metabolism; Disease Models, Animal; Drosophila melanogaster/genetics; Drosophila melanogaster/metabolism; Female; Humans; Inclusion Bodies/metabolism; Inclusion Bodies/pathology; Male; Microscopy, Electron; Microtubules/metabolism; Microtubules/pathology; Nervous System/metabolism; Nervous System/pathology; Nervous System/physiopathology; Neurons/metabolism; Neurons/pathology; Phosphorylation/drug effects; Protein Binding/physiology; Solubility; Tauopathies/metabolism; Tauopathies/pathology; Tauopathies/physiopathology; tau Proteins/genetics; tau Proteins/metabolism; tau Proteins/toxicity

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:A0A0B4KHQ8

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4KI45

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4LHR7

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4LHS3

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4LHV0

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4LIS6

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A0B4LIT4

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:A0A126GV16

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:D3DMW4

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q9VB15

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q9VB13

colocalizes_with

GO:0005881: cytoplasmic microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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