Vinexin contributes to autophagic decline in brain ageing across species
Park, So Jung
Cell Death and Differentiation
Springer Nature [academic journals on nature.com]
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Rubinsztein, D., Park, S. J., Frake, R., Karabiyik, C., Son, S., Siddiqi, F., Bento, C., et al. (2021). Vinexin contributes to autophagic decline in brain ageing across species. Cell Death and Differentiation https://doi.org/10.1038/s41418-021-00903-y
Autophagic decline is considered a hallmark of ageing. The activity of this intracytoplasmic degradation pathway decreases with age in many tissues and autophagy induction ameliorates ageing in many organisms, including mice. Autophagy is a critical protective pathway in neurons and ageing is the primary risk factor for common neurodegenerative diseases. Here, we describe that autophagosome biogenesis declines with age in mouse brains and that this correlates with increased expression of the SORBS3 gene (encoding vinexin) in older mouse and human brain tissue. We characterise vinexin as a negative regulator of autophagy. SORBS3 knockdown increases F-actin structures, which compete with YAP/TAZ for binding to their negative regulators, angiomotins, in the cytosol. This promotes YAP/TAZ translocation into the nucleus, thereby increasing YAP/TAZ transcriptional activity and autophagy. Our data therefore suggest brain autophagy decreases with age in mammals and that this is likely, in part, mediated by increasing levels of vinexin.
Funding for this study was obtained from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), the Roger de Spoelberch Foundation, the Cambridge Centre for Parkinson-Plus, the Wellcome Trust [095317/Z/11/Z and 100140/Z/12/Z] and the NEUROMICS project (European Community’s Seventh Framework Programme under grant agreement number 2012-305121). In addition, R.A.F. received funding through the University of Cambridge MB/PhD Programme (Sims Scholarship, James Baird Fund and the Frank Edward Elmore Fund), C.K. received funding from a Gates Cambridge Scholarship and M.P. received a grant of the Romanian Ministry of Research, Innovation and Digitization, CNCS/CCCDI-UEFISCDI, project number PN-III-P1-1.1-PD-2019-0733, within PNCDI-III and POC/448/1/1/127606 CENEMED project.
Wellcome Trust (095317/Z/11/Z)
External DOI: https://doi.org/10.1038/s41418-021-00903-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336109
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/