Paired Helical Filament-Forming Region of Tau (297-391) Influences Endogenous Tau Protein and Accumulates in Acidic Compartments in Human Neuronal Cells
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved..
Assembly of tau protein into paired helical filaments and straight filaments is a key feature of Alzheimer's disease. Aggregation of tau has been implicated in neurodegeneration, cellular toxicity and the propagation, which accompanies disease progression. We have reported previously that a region of tau (297-391), referred to as dGAE, assembles spontaneously in physiological conditions to form paired helical filament-like fibres in vitro in the absence of additives such as heparin. This provides a valuable tool with which to explore the effects of tau in cell culture. Here we have studied the cellular uptake of soluble oligomeric and fibrillar forms of dGAE and examined the downstream consequences of tau internalisation into differentiated SH-SY5Y neuroblastoma cells using fluorescence and electron microscopy alongside structural and biochemical analyses. The assembled dGAE shows more acute cytotoxicity than the soluble, non-aggregated form. Conversely, the soluble form is much more readily internalised and, once within the cell, is able to associate with endogenous tau resulting in increased phosphorylation and aggregation of endogenous tau, which accumulates in lysosomal/endosomal compartments. It appears that soluble oligomeric forms are able to propagate tau pathology without being acutely toxic. The model system we have developed now permits the molecular mechanisms of propagation of tau pathology to be studied in vitro in a more physiological manner with a view to development of novel therapeutic approaches.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:432 |
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| Enthalten in: |
Journal of molecular biology - 432(2020), 17 vom: 07. Aug., Seite 4891-4907 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pollack, Saskia J [VerfasserIn] |
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| Links: |
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| Themen: |
9005-49-6 |
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| Anmerkungen: |
Date Completed 25.01.2021 Date Revised 24.09.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jmb.2020.05.027 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312581645 |
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| 520 | |a Assembly of tau protein into paired helical filaments and straight filaments is a key feature of Alzheimer's disease. Aggregation of tau has been implicated in neurodegeneration, cellular toxicity and the propagation, which accompanies disease progression. We have reported previously that a region of tau (297-391), referred to as dGAE, assembles spontaneously in physiological conditions to form paired helical filament-like fibres in vitro in the absence of additives such as heparin. This provides a valuable tool with which to explore the effects of tau in cell culture. Here we have studied the cellular uptake of soluble oligomeric and fibrillar forms of dGAE and examined the downstream consequences of tau internalisation into differentiated SH-SY5Y neuroblastoma cells using fluorescence and electron microscopy alongside structural and biochemical analyses. The assembled dGAE shows more acute cytotoxicity than the soluble, non-aggregated form. Conversely, the soluble form is much more readily internalised and, once within the cell, is able to associate with endogenous tau resulting in increased phosphorylation and aggregation of endogenous tau, which accumulates in lysosomal/endosomal compartments. It appears that soluble oligomeric forms are able to propagate tau pathology without being acutely toxic. The model system we have developed now permits the molecular mechanisms of propagation of tau pathology to be studied in vitro in a more physiological manner with a view to development of novel therapeutic approaches | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Alzheimer's disease | |
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| 700 | 1 | |a Khanom, Tahmida |e verfasserin |4 aut | |
| 700 | 1 | |a Biasetti, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Marshall, Karen E |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Hilaly, Youssra K |e verfasserin |4 aut | |
| 700 | 1 | |a Rickard, Janet E |e verfasserin |4 aut | |
| 700 | 1 | |a Harrington, Charles R |e verfasserin |4 aut | |
| 700 | 1 | |a Wischik, Claude M |e verfasserin |4 aut | |
| 700 | 1 | |a Serpell, Louise C |e verfasserin |4 aut | |
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