A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration

Abstract

Alzheimer's disease (AD, OMIM: 104300) is an age-related disorder that affects millions of people. One of the underlying causes of AD is generation of hydrophobic amyloid-beta 42 (Aβ42) peptides that accumulate to form amyloid plaques. These plaques induce oxidative stress and aberrant signaling, which result in the death of neurons and other pathologies linked to neurodegeneration. We have developed a Drosophila eye model of AD by targeted misexpression of human Aβ42 in the differentiating retinal neurons, where an accumulation of Aβ42 triggers a characteristic neurodegenerative phenotype. In a forward deficiency screen to look for genetic modifiers, we identified a molecularly defined deficiency, which suppresses Aβ42-mediated neurodegeneration. This deficiency uncovers hippo (hpo) gene, a member of evolutionarily conserved Hippo signaling pathway that regulates growth. Activation of Hippo signaling causes cell death, whereas downregulation of Hippo signaling triggers cell proliferation. We found that Hippo signaling is activated in Aβ42-mediated neurodegeneration. Downregulation of Hippo signaling rescues the Aβ42-mediated neurodegeneration, whereas upregulation of Hippo signaling enhances the Aβ42-mediated neurodegeneration phenotypes. It is known that c-Jun-amino-terminal kinase (JNK) signaling pathway is upregulated in AD. We found that activation of JNK signaling enhances the Aβ42-mediated neurodegeneration, whereas downregulation of JNK signaling rescues the Aβ42-mediated neurodegeneration. We tested the nature of interactions between Hippo signaling and JNK signaling in Aβ42-mediated neurodegeneration using genetic epistasis approach. Our data suggest that Hippo signaling and JNK signaling, two independent signaling pathways, act synergistically upon accumulation of Aβ42 plaques to trigger cell death. Our studies demonstrate a novel role of Hippo signaling pathway in Aβ42-mediated neurodegeneration.

A Two-Clone Approach to Study Signaling Interactions among Neuronal Cells in a Pre-clinical Alzheimer's Disease Model

“…Previous research in flies and humans has implicated activation of the highly conserved JNK signaling pathway in AD ( Irwin et al., 2020 ; Sarkar et al., 2018 ; Tare et al., 2011 ; Wang et al., 2014 ; Yarza et al., 2015 ). Phosphorylation of JNK transcriptionally activates apoptosis, and increased levels of pJNK have been reported in patients with AD ( Wang et al., 2014 ).…”

“…In humans and AD models, Aβ42 accumulation is linked to increases in activation of the JNK pathway ( Irwin et al., 2020 ; Ray et al., 2017 ; Sarkar et al., 2018 ; Tare et al., 2011 ; Wang et al., 2014 ; Yarza et al., 2015 ). The JNK signaling pathway, part of the mitogen-activated protein kinase (MAPK) superfamily, is highly conserved and transcriptionally activates apoptosis.…”

“…Research in both flies and humans has implicated activation of the JNK signaling pathway in AD and other neurodegenerative disorders ( Gogia et al., 2020b ; Irwin et al., 2020 ; Tare et al., 2011 ; Wang et al., 2014 ; Yarza et al., 2015 ). JNK signaling has also been connected to a conserved process known as cell competition, which is involved in maintaining tissue homeostasis.…”

Motif 1 Binding Protein suppresses wingless to promote eye fate in Drosophila

“…Adult eye images were captured after freezing flies at − 20 °C for ~ 4 h. Images were taken on a MrC5 color camera mounted on an Axioimager.Z1 Zeiss Apotome using a Z-sectioning function of Axiovision software 4.6.3 71 . The final images were prepared using Adobe Photoshop CS6 software.…”

Pharmacological Treatment of Alzheimer’s Disease: Insights from Drosophila melanogaster

“…In Drosophila, researchers expressed high levels of human Aβ42 polypeptide in the differentiating photoreceptor neurons and developed a transgenic model system in Drosophila eye [111]. A Chinese traditional medicinal prescription called KSOP1009 could strongly suppress Aβ42-induced eye degeneration and the locomotive dysfunctions via suppression of the hyperactivation of JNK activity and apoptosis [112]. A recent study found a positive feedback loop of Hippo and JNK signaling which regulates Aβ mediated neurodegeneration.…”