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Tau-mediated axonal degeneration is prevented by activation of the WldS pathway

Tau-mediated axonal degeneration is prevented by activation of the WldS pathway
Tau-mediated axonal degeneration is prevented by activation of the WldS pathway
Tauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau. The neuronal changes evident in Tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by expression of WldS. In a Drosophila model of tauopathy in which expression of human Tau protein (hTau0N3R) leads to progressive age-dependent phenotypes, activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after hTau-mediated degeneration had become established. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in hTau0N3R –expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by hTau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.
Stubbs, Katy
5e5b95de-e497-432d-8bc9-d3bc95919fb6
Sealey, Megan A
c4545b95-18e2-47fe-8535-9d14e1aed991
Ramirez Moreno, Miguel
ccfb4355-2fa6-4058-9dfe-1c246845a4bb
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Newman, Tracey
322290cb-2e9c-445d-a047-00b1bea39a25
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Stubbs, Katy
5e5b95de-e497-432d-8bc9-d3bc95919fb6
Sealey, Megan A
c4545b95-18e2-47fe-8535-9d14e1aed991
Ramirez Moreno, Miguel
ccfb4355-2fa6-4058-9dfe-1c246845a4bb
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Newman, Tracey
322290cb-2e9c-445d-a047-00b1bea39a25
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119

Stubbs, Katy, Sealey, Megan A, Ramirez Moreno, Miguel, Perry, V. Hugh, Newman, Tracey and Mudher, Amritpal (2020) Tau-mediated axonal degeneration is prevented by activation of the WldS pathway. bioRxiv. (doi:10.1101/2020.12.06.408583). (In Press)

Record type: Article

Abstract

Tauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau. The neuronal changes evident in Tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by expression of WldS. In a Drosophila model of tauopathy in which expression of human Tau protein (hTau0N3R) leads to progressive age-dependent phenotypes, activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after hTau-mediated degeneration had become established. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in hTau0N3R –expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by hTau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.

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Accepted/In Press date: 11 December 2020

Identifiers

Local EPrints ID: 447460
URI: http://eprints.soton.ac.uk/id/eprint/447460
PURE UUID: 288f03d1-ebd4-410c-8a02-37bbdd7896f4
ORCID for Tracey Newman: ORCID iD orcid.org/0000-0002-3727-9258

Catalogue record

Date deposited: 11 Mar 2021 17:37
Last modified: 12 Mar 2021 02:35

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Contributors

Author: Katy Stubbs
Author: Megan A Sealey
Author: Miguel Ramirez Moreno
Author: V. Hugh Perry
Author: Tracey Newman ORCID iD
Author: Amritpal Mudher

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