Tau-mediated axonal degeneration is prevented by activation of the Wld S pathway.

Autor:	Stubbs K; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Batchelor B; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Sivanantharajah L; School of Biological Sciences, Bangor University, Bangor LL57 2UW, UK., Sealey M; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Ramirez-Moreno M; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Ruiz E; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Richardson B; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Perry VH; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK., Newman TA; Clinical and Experimental Science, Faculty of Medicine, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK., Mudher A; School of Biological Sciences, Faculty of Environment and Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2023 Mar 09; Vol. 5 (2), pp. fcad052. Date of Electronic Publication: 2023 Mar 09 (Print Publication: 2023).
DOI:	10.1093/braincomms/fcad052
Abstrakt:	Tauopathy is characterized 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 (Wld S ) 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 co-expression of Wld S . In a Drosophila model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, Wld S was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit OR47b was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of Wld S completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of Wld S was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, Wld S 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 tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of Wld S intersects with the mechanism(s) of degeneration initiated by tau 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. Competing Interests: The authors declare no conflicts of interest. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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