Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes

Abstract

Cilia are dynamic microtubule-based organelles present on the surface of many eukaryotic cell types and can be motile or non-motile primary cilia. Cilia defects underlie a growing list of human disorders, collectively called ciliopathies, with overlapping phenotypes such as developmental delays and cognitive and memory deficits. Consistent with this, cilia play an important role in brain development, particularly in neurogenesis and neuronal migration. These findings suggest that a deeper systems-level understanding of how ciliary proteins function together may provide new mechanistic insights into the molecular etiologies of nervous system defects. Towards this end, we performed a protein-protein interaction (PPI) network analysis of known intraflagellar transport, BBSome, transition zone, ciliary membrane and motile cilia proteins. Known PPIs of ciliary proteins were assembled from online databases. Novel PPIs were predicted for each ciliary protein using a computational method we developed, called High-precision PPI Prediction (HiPPIP) model. The resulting cilia "interactome" consists of 165 ciliary proteins, 1,011 known PPIs, and 765 novel PPIs. The cilia interactome revealed interconnections between ciliary proteins, and their relation to several pathways related to neuropsychiatric processes, and to drug targets. Approximately 184 genes in the cilia interactome are targeted by 548 currently approved drugs, of which 103 are used to treat various diseases of nervous system origin. Taken together, the cilia interactome presented here provides novel insights into the relationship between ciliary protein dysfunction and neuropsychiatric disorders, for e.g. interconnections of Alzheimer's disease, aging and cilia genes. These results provide the framework for the rational design of new therapeutic agents for treatment of ciliopathies and neuropsychiatric disorders.

Figure 1

Cilia interactome. Cilia genes are shown as small dark-blue colored nodes and interactor genes are larger round nodes; the interactors are colored in light blue if they are previously known interactors and in red if they are found only through novel PPIs. PPIs are shown as edges, where blue color edges are known PPIs and red color edges are novel predicted PPIs. Most genes at the bottom of the figure have had zero known PPIs, and have multiple novel predicted PPIs.

Figure 2

Number of drugs targeting genes in the cilia interactome. The numbers are shown separated by the anatomic category of the drugs (anatomic, therapeutic and chemical classification) and also separated by whether they target known interactors (blue) or novel interactors (red) or both (cream-colored).

Figure 3

Interconnections between cilia, aging and Alzheimer’s disease genes. Cilia genes are shown as red nodes; AD genes are colored in cyan and aging genes in green. PPIs are shown as edges, where grey edges are known PPIs and red color edges are novel predicted PPIs. Genes with bold labels are involved in the sonic hedgehog (Shh) pathway and those with blue labels are involved in neurogenesis. Note that, in this case, a bold blue-labeled gene indicates a cilia gene with Shh involvement, which is also involved in neurogenesis.

Figure 4

Direction of fold change of gene expression levels in AD vs. non-AD hippocampal samples compared with expression at 40 years vs. 8 post-conceptional weeks. The X-axis shows the 67 genes that are differentially expressed in the hippocampus of Alzheimer’s disease patients compared with the hippocampus of healthy subjects. The red bars on the Y-axis show the fold change of the differential expression of these genes in AD vs. non-AD hippocampal samples. The blue bars on the Y-axis show the fold change in the expression level of these genes in normal hippocampus at 40 years after birth (middle adulthood) compared with 8 weeks after conception (fetal life) in healthy humans.