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Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

ABSTRACT: Wnt signaling has well established roles in development and cancer progression. Its roles during normal adult homeostasis are less well studied, but Wnt is a major stem cell regulating factor in adult tissues. Here we use an optogenetic model of amyloid beta aggregation to examine the effect of Wnt signaling on protein aggregation. We observe that Wnt activation rescues the detrimental effects of Amyloid. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find a protein misfolding response and a metabolic response, but the major factor we focus on is inflammation. Wnt expression reduces inflammation through repression of Toll activating factors, and chronic Toll activation reduces lifespan. We propose that the protective effect observed for lithium treatment functions at least in part through Wnt activation and inhibition of inflammation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE181844 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:INTRODUCTION: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention.</br>OBJECTIVES:To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states.</br>METHOD: Neuroblastoma SH-SY5Y cells were employed to design a robust routine system to perform a statistically rigorous NMR metabolomics study into cellular effects of sub-toxic levels of alpha-synuclein, amyloid-beta 40 and amyloid-beta 42 in monomeric, oligomeric and fibrillar conformations.</br>RESULTS: This investigation developed a rigorous model to monitor intracellular metabolic profiles of neuronal cells through combination of existing methods. This model revealed eight key metabolites that are altered when neuroblastoma cells are challenged with proteins in different aggregation states. Metabolic pathways associated with lipid metabolism, neurotransmission and adaptation to oxidative stress and inflammation are the predominant contributors to the cellular variance and intracellular metabolite levels. The observed metabolite changes for monomer and oligomer challenge may represent cellular effort to counteract the pathogenicity of the challenge, whereas fibrillar challenge is indicative of system shutdown. This implies that although markers of stress are more prevalent under oligomeric challenge the fibrillar response suggests a more toxic environment.</br>CONCLUSION: This approach is applicable to any cell type that can be cultured in a laboratory (primary or cell line) as a method of investigating how protein challenge affects signalling pathways, providing additional understanding as to the role of protein aggregation in neurodegenerative disease initiation and progression.

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Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

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