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Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson’s disease associated with enhanced autophagy

Lookup NU author(s): Dr Tengfei Wan, Mary Johnson, Dr Viktor Korolchuk, Dr Gabriele Saretzki

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Protective effects of the telomerase protein TERT have been shown in neurons and brain. We previously demonstrated that TERT protein can accumulate in mitochondria of Alzheimer’s disease (AD) brains and protect from pathological tau in primary mouse neurons. This prompted us to employ telomerase activators in order to boost telomerase expression in a mouse model of Parkinson’s disease (PD) overexpressing human wild type a-synuclein. Our aim was to test whether increased Tert expression levels were able to ameliorate PD symptoms and to activate protein degradation. We found increased Tert expression in brain for both activators which correlated with a substantial improvement of motor functions such as gait and motor coordination while telomere length in the analysed region was not changed. Interestingly, only one activator (TA-65) resulted in a decrease of reactive oxygen species from brain mitochondria. Importantly, we demonstrate that total, phosphorylated and aggregated a-synuclein were significantly decreased in the hippocampus and neocortex of activator-treated mice corresponding to enhanced markers of autophagy suggesting an improved degradation of toxic alpha-synuclein. We conclude that increased Tert expression caused by telomerase activators is associated with decreased a-synuclein protein levels either by activating autophagy or by preventing or delaying degradation mechanisms which are impaired during disease progression. This encouraging preclinical data could be translated into novel therapeutic options for neurodegenerative disorders such as PD.


Publication metadata

Author(s): Wan T, Weir EJ, Johnson M, Korolchuk VI, Saretzki GC

Publication type: Article

Publication status: Published

Journal: Progress in Neurobiology

Year: 2021

Volume: 199

Print publication date: 01/04/2021

Online publication date: 11/11/2020

Acceptance date: 08/11/2020

Date deposited: 12/11/2020

ISSN (print): 0301-0082

Publisher: Elsevier

URL: https://doi.org/10.1016/j.pneurobio.2020.101953

DOI: 10.1016/j.pneurobio.2020.101953


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