Willin/FRMD6 mediates mitochondrial dysfunction relevant to neuronal Aβ toxicity
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Willin/FRMD6 has been reported as a potential Alzheimer’s disease risk gene in a series of genome-wide association and neuroimaging studies; however, the mechanisms underlying its potential role in AD pathogenesis remain unknown. Here, we demonstrate the direct effects of Aβ on Willin/FRMD6 expression and position mitochondrial oxidative stress as a novel potential mechanism underlying the role of Willin/FRMD6 in AD pathogenesis. Specifically, using mouse hippocampal HT-22 cells and primary mouse neurons, we show that Aβ induces downregulation of the Willin/FRMD6 protein. Furthermore, we demonstrate that Willin/FRMD6 knockdown leads to mitochondrial dysfunction and fragmentation, as well as upregulation of ERK1/2 signaling, both of which are reported to be key early features of AD pathogenesis. Importantly, increasing Willin/FRMD6 expression was able to rescue Aβ-induced abnormalities in mitochondrial morphology, function, and energetics. Thus, enhancing Willin/FRMD6 expression holds potential as a therapeutic strategy for protecting against Aβ-induced mitochondrial and neuronal dysfunction.
Chen , D , Yu , W , Aitken , L & Gunn-Moore , F J 2022 , ' Willin/FRMD6 mediates mitochondrial dysfunction relevant to neuronal Aβ toxicity ' , Cells , vol. 11 , no. 19 , 3140 . https://doi.org/10.3390/cells11193140
Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
DescriptionThis study was supported by the EPSRC (EP/P030017), Alzheimer’s Research UK, the Rosetrees Trust, and the China Scholarship Council.
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