Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

Tau is a highly soluble protein, yet it aggregates abnormally in Alzheimer's disease. Here, we address the question of proteolytic processing of tau and the nucleation of aggregates by tau fragments. We show in neuronal cell models that fragments of the repeat domain of tau containing mutations...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2007-06, Vol.104 (24), p.10252-10257
Hauptverfasser: Wang, Y.P, Biernat, J, Pickhardt, M, Mandelkow, E, Mandelkow, E.-M
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container_end_page 10257
container_issue 24
container_start_page 10252
container_title Proceedings of the National Academy of Sciences - PNAS
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creator Wang, Y.P
Biernat, J
Pickhardt, M
Mandelkow, E
Mandelkow, E.-M
description Tau is a highly soluble protein, yet it aggregates abnormally in Alzheimer's disease. Here, we address the question of proteolytic processing of tau and the nucleation of aggregates by tau fragments. We show in neuronal cell models that fragments of the repeat domain of tau containing mutations of FTDP17 (frontotemporal dementia with parkinsonism linked to chromosome 17), produced by endogenous proteases, can induce the aggregation of full-length tau. Fragments are generated by successive cleavages, first N-terminally between K257 and S258, then C-terminally around residues 353-364; conversely, when the N-terminal cleavage is inhibited, no fragmentation and aggregation takes place. The C-terminal truncation and the coaggregation of fragments with full-length tau depends on the propensity for β-structure. The aggregation is modulated by phosphorylation but does not depend on it. Aggregation but not fragmentation as such is toxic to cells; conversely, toxicity can be prevented by inhibiting either aggregation or proteolysis. The results reveal a novel pathway of abnormal tau aggregation in neuronal cells.
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Here, we address the question of proteolytic processing of tau and the nucleation of aggregates by tau fragments. We show in neuronal cell models that fragments of the repeat domain of tau containing mutations of FTDP17 (frontotemporal dementia with parkinsonism linked to chromosome 17), produced by endogenous proteases, can induce the aggregation of full-length tau. Fragments are generated by successive cleavages, first N-terminally between K257 and S258, then C-terminally around residues 353-364; conversely, when the N-terminal cleavage is inhibited, no fragmentation and aggregation takes place. The C-terminal truncation and the coaggregation of fragments with full-length tau depends on the propensity for β-structure. The aggregation is modulated by phosphorylation but does not depend on it. Aggregation but not fragmentation as such is toxic to cells; conversely, toxicity can be prevented by inhibiting either aggregation or proteolysis. 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subjects Aggregation
Alzheimer Disease - metabolism
Alzheimer's disease
Amino Acid Motifs
Amino Acid Sequence
Amino Acid Substitution
Animals
Antibodies
Binding Sites
Biological Sciences
Brain
Cell aggregates
Cell Line, Tumor
Cell lines
Centrifugation
Delta cells
Epitopes
Fluorescent Antibody Technique, Indirect
Humans
Hydrolysis
Mice
Microscopy, Fluorescence
Models, Biological
Models, Chemical
Neuroblastoma - pathology
Neurons
Neurons - metabolism
Neurosciences
Peptide Fragments - metabolism
Peptide Hydrolases - chemistry
Peptide Hydrolases - metabolism
Phosphorylation
Protein Binding
Protein Conformation
Protein Isoforms
Protein Processing, Post-Translational
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins
Proteomics
Solubility
tau Proteins - chemistry
tau Proteins - genetics
tau Proteins - metabolism
Thrombin - chemistry
title Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model
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