Bradshaw, Aaron;
(2018)
The Analysis of Exosomal Tau Release and its Regulation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The secretion of Tau protein from cells combined with its trans-cellular uptake has been hypothesised as a central component in the progression of Tauopathic neurodegenerative diseases. Exosomes, small (30 – 140 nm) vesicles released from cells, may represent a privileged route for secretion and transmission of neurodegenerative proteins. We hypothesised that 1) Tau protein may be released from cells in exosomes 2) that this process may be regulated by the interaction of Tau with the chaperone network and SUMOylation of Tau and 3) exosomes may transmit Tau to naïve cells. We established and characterised the exosomal release of Tau from SH-SY5Y cells; all isoforms of Tau studied, including endogenous SH-SY5Y Tau, were detected in exosomal fractions. Exosomal 2N4R-Tau was C-terminally truncated and intra-luminal. We investigated the role of Tau-Hsc70 interaction in its exosomal release and identified the co-chaperone DNAjC5 as a key mediator in this process. SUMOylation of Tau protein was also identified as a key process regulating its exosomal release. We furthermore gathered evidence connecting Tau protein dysfunction (P301L-Tau; oligomerisation) and exosomal release, implicating exosomal Tau release as a potentially disease relevant process. In order to model the transmission of Tau between cells, we studied the uptake of a) Tau recovered from cells and b) Tau secreted from cells. However, naïve SH-SY5Y cells were able to internalise extracellular Tau only to a low extent. When co-cultured, Tau protein transferred efficiently between cells. This process was potentiated by lysosomal compromise and dependent upon cell density. Finally, we determined that exosomes isolated from SH-SY5Y cells with ectopic expression of P301L-Tau were selectively toxic to primary mouse cortical neurons. Overall the work presented here confirms the exosomal release of Tau protein and links this process to pathological Tau. Our work identifies key cellular mechanisms governing the exosomal release of Tau that may serve as points of departure for future studies investigating the release and transmission of Tau, and the role of exosomes therein.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Analysis of Exosomal Tau Release and its Regulation |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Tau Transmission Exosomes Pathology Secretion Propagation Isoforms |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10062627 |
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