Exploring the conservation of Alzheimer-related pathways between H. sapiens and C. elegans: a network alignment approach

Abstract

Alzheimer disease (AD) is a neurodegenerative disorder with an -as of yet- unclear etiology and pathogenesis. Research to unveil disease processes underlying AD often relies on the use of neurodegenerative disease model organisms, such as Caenorhabditis elegans. This study sought to identify biological pathways implicated in AD that are conserved in Homo sapiens and C. elegans. Protein-protein interaction networks were assembled for amyloid precursor protein (APP) and Tau in H. sapiens-two proteins whose aggregation is a hallmark in AD-and their orthologs APL-1 and PTL-1 for C. elegans. Global network alignment was used to compare these networks and determine similar, likely conserved, network regions. This comparison revealed that two prominent pathways, the APP-processing and the Tau-phosphorylation pathways, are highly conserved in both organisms. While the majority of interactions between proteins in those pathways are known to be associated with AD in human, they remain unexamined in C. elegans, signifying the need for their further investigation. In this work, we have highlighted conserved interactions related to AD in humans and have identified specific proteins that can act as targets for experimental studies in C. elegans, aiming to uncover the underlying mechanisms of AD.

Figure 1

Alignment of human APP and Tau network from Amyloid Interactome and homologous C. elegans network by MAGNA++ with combination of biological and topological information, containing both correct and incorrect alignments. The human network (top) and the C. elegans network (bottom) are displayed with the layout of nodes corresponding to the predicted ortholog mapping. Human proteins with no predicted orthologs in the C. elegans network are isolated on the upper side of the human network. Two dotted black lines show the positioning of ortholog pairs APP & APL-1 and Tau & PTL-1 that were not correctly aligned; APP and Tau were not mapped to any C. elegans protein, while APL-1 and PTL-1 were aligned with RNF32 and PRAM1, respectively. All node alignments are available in Supplementary Table 3. Groups of nodes surrounded by dotted lines represent proteins mapped to the same predicted ortholog. These protein nodes have been colored accordingly, to make it easier to detect. Detailed information about the proteins in these networks can be retrieved via the web application (http://thalis.biol.uoa.gr/celegans_human_AD/).

Figure 2

Alignments for the “APL-1and PTL-1 network from STRING” and the “Top 100 interaction partners” datasets and their common elements. (a) The C. elegans APL-1 and PTL-1 network from STRING (green) and the homologous human network (blue), with the unified network resulting from their alignment below. (b) The Top 100 interaction partners of APL-1 and PTL-1 for the C. elegans network (green) and of APP and Tau for the human network (blue). Below these networks is the unified network resulting from their alignment. (c) The common elements of the two unified networks (pairs of proteins and their PPIs aligned similarly in both datasets). Omics Visualizer was used to apply colors on the network’s nodes, with the green half representing the C. elegans protein and the blue half representing the human protein. Each half is labeled with their corresponding gene symbol (gene symbol for Tau is MAPT). All human interactions were annotated with at least one supporting publication (Supplementary Table 4); edges with underlined labels indicate annotations directly associated with AD. On the contrary, only one C. elegans interaction could be annotated as AD related based on literature evidence.

Figure 3

Conservation of the APP processing pathway in H. sapiens and C. elegans. Shown here are elements of the APP processing pathway found in the Common Network, extended with relevant proteins and interactions from the “Top 100 interaction partners” dataset. Elements associated with α- and γ-secretase activity are conserved in both organisms, while β-secretase is missing from C. elegans. Even though all interactions that take place in this pathway have been experimentally investigated in human, information related to AD could be retrieved only for two C. elegans interactions.

Figure 4

AD associated phosphorylation-related proteins conserved in H. sapiens and C. elegans. Shown here are elements related to phosphorylation of APP and Tau found in the Common Network, extended with relevant proteins and interactions from the “Top 100 interaction partners” dataset. The interactions appear to be conserved in both organisms, but no information was available for the C. elegans interactions. The gene symbol for Tau is MAPT.