Willin/FRMD6 mediates mitochondrial dysfunction relevant to neuronal Aβ toxicity

Abstract

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.