Microtubule decay is a driver of neuronal ageing and a promising target for intervention

Okenve-Ramos, Pilar ORCID: 0000-0002-7513-6557, Gosling, Rory, Chojnowska-Monga, Monika ORCID: 0000-0002-3373-3169, Gupta, Kriti ORCID: 0000-0002-1394-1518, Shields, Samuel and Sanchez-Soriano, Natalia ORCID: 0000-0002-6667-2817
(2023) Microtubule decay is a driver of neuronal ageing and a promising target for intervention. [Preprint]

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<jats:title>Abstract</jats:title><jats:p>Natural ageing is accompanied by a decline in motor, sensory and cognitive functions, all impacting life quality. Ageing is the predominant risk factor for many neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease. We need therefore to gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the long time required to age mammalian or vertebrate model animals.</jats:p><jats:p>Here we introduce a new cellular model within the<jats:italic>Drosophila</jats:italic>brain where neurons show typical ageing hallmarks known from the primate brain, including axonal swellings, cytoskeletal decay, a reduction in axonal calibre and morphological changes arising at synaptic terminals. In the fly brain, these changes occur within just a few weeks, ideal to study the underlying mechanisms. We observe that decay of the neuronal microtubule cytoskeleton clearly precedes other ageing hallmarks. We show that the microtubule-binding factors Tau, EB1 and Shot, are necessary for microtubule maintenance in axons and synapses. Their functional loss during ageing triggers microtubule bundle decay followed by the decline in axons and synapses. Genetic manipulations that improve microtubule networks, slow down other neuronal ageing hallmarks and confer aged specimens with the ability to outperform age-matched controls. Our work suggests therefore that microtubule networks are a key lesion site in ageing neurons and offer promising opportunities to improve neuronal decay in advanced age.</jats:p>

Item Type: Preprint
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 01 Feb 2023 14:48
Last Modified: 01 Feb 2023 14:48
DOI: 10.1101/2023.01.11.523590
Open Access URL: https://doi.org/10.1101/2023.01.11.523590
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3168076