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Microtubule stabilising peptides rescue tau phenotypes in-vivo

Microtubule stabilising peptides rescue tau phenotypes in-vivo
Microtubule stabilising peptides rescue tau phenotypes in-vivo
The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease.
Quraishe, Shmma
cfc3aed4-f120-41aa-9127-0fc26c657ad2
Sealey, Megan
f4f4e7b5-b160-434c-b5e7-a6468283bfdd
Cranfield, Louise
5453b2ad-7247-4f09-bb6c-3a380be12255
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Quraishe, Shmma
cfc3aed4-f120-41aa-9127-0fc26c657ad2
Sealey, Megan
f4f4e7b5-b160-434c-b5e7-a6468283bfdd
Cranfield, Louise
5453b2ad-7247-4f09-bb6c-3a380be12255
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119

Quraishe, Shmma, Sealey, Megan, Cranfield, Louise and Mudher, Amritpal (2016) Microtubule stabilising peptides rescue tau phenotypes in-vivo. Scientific Reports, 6, [38224]. (doi:10.1038/srep38224). (PMID:27910888)

Record type: Article

Abstract

The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease.

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Accepted/In Press date: 7 November 2016
e-pub ahead of print date: 2 December 2016
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 404579
URI: http://eprints.soton.ac.uk/id/eprint/404579
PURE UUID: 08e09da4-5680-4653-bfd8-42b4c56cbe42

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Date deposited: 12 Jan 2017 09:30
Last modified: 26 Feb 2020 17:30

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Contributors

Author: Shmma Quraishe
Author: Megan Sealey
Author: Louise Cranfield
Author: Amritpal Mudher

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