School of Biology, University of St Andrews, St Andrews KY16 9TF, UK.
Cells. 2022 Oct 6;11(19):3140. doi: 10.3390/cells11193140.
Willin/ has been reported as a potential Alzheimer's disease (AD) 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 Willin/FRMD6 protein expression. 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.
威林/已被报道为一系列全基因组关联和神经影像学研究中的阿尔茨海默病（AD）潜在风险基因；然而，其在 AD 发病机制中的潜在作用的机制仍不清楚。在这里，我们证明了 Aβ对威林/FRMD6 表达的直接影响，并将线粒体氧化应激定位为威林/FRMD6 在 AD 发病机制中作用的新的潜在机制。具体来说，我们使用小鼠海马 HT-22 细胞和原代小鼠神经元，表明 Aβ诱导威林/FRMD6 蛋白表达下调。此外，我们证明威林/FRMD6 敲低导致线粒体功能障碍和碎片化，以及 ERK1/2 信号的上调，这两者都被报道为 AD 发病机制的关键早期特征。重要的是，增加威林/FRMD6 的表达能够挽救 Aβ诱导的线粒体和神经元功能障碍。因此，增强威林/FRMD6 的表达可能成为一种保护 Aβ诱导的线粒体和神经元功能障碍的治疗策略。
