Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Abstract

Recent advances toward the characterization of Alzheimer's disease (AD) have permitted the identification of a dozen of genetic risk factors, although many more remain undiscovered. In parallel, works in the field of network biology have shown a strong link between protein connectivity and disease. In this manuscript, we demonstrate that AD-related genes are indeed highly interconnected and, based on this observation, we set up an interaction discovery strategy to unveil novel AD causative and susceptibility genes. In total, we report 200 high-confidence protein-protein interactions between eight confirmed AD-related genes and 66 candidates. Of these, 31 are located in chromosomal regions containing susceptibility loci related to the etiology of late-onset AD, and 17 show dysregulated expression patterns in AD patients, which makes them very good candidates for further functional studies. Interestingly, we also identified four novel direct interactions among well-characterized AD causative/susceptibility genes (i.e., APP, A2M, APOE, PSEN1, and PSEN2), which support the suggested link between plaque formation and inflammatory processes and provide insights into the intracellular regulation of APP cleavage. Finally, we contextualize the discovered relationships, integrating them with all the interaction data reported in the literature, building the most complete interactome associated to AD. This general view facilitates the analyses of global properties of the network, such as its functional modularity, and triggers many hypotheses on the molecular mechanisms implicated in AD. For instance, our analyses suggest a putative role for PDCD4 as a neuronal death regulator and ECSIT as a molecular link between oxidative stress, inflammation, and mitochondrial dysfunction in AD.

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

“…With the additional complex V, the OXPHOS system becomes functional, which is crucial for cell bioenergetics. Interactions in our AD-PIN network [9] revealed that ECSIT is also functionally connected with well-established AD causative genes (see Table 1). The position of ECSIT in this molecular circuitry indicates that it functions as an integrating hub that may constitute a molecular switch to soothe/exacerbate amyloid pathology (see the legend for details of symbols.…”

“…However, besides the APOE-e4 gene, very few associations could be established with specific genes [42]. Therefore, in an attempt to identify novel genes in this locus, we applied an interaction discovery approach to generate an AD-associated protein interaction network (AD-PIN), based on our previous findings that AD causative and susceptibility genes tend to be physically connected [9]. We discovered 200 novel protein-protein interactions between AD causative and susceptibility gene products.…”

“…In our quest to uncover potential causative/susceptibility genes related to the disease, we identified evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) as a promising candidate underlying AD mechanisms [9]. It encodes for an adapter protein that intersects the immune toll-like receptor (TLR) and the homeostatic bone morphogenetic pathway (BMP)/transforming growth factor-beta (TGF-b) signalling pathways [10].…”

From protein interaction networks to novel therapeutic strategies

“…Validating a number of interaction partners retrieved from the network in Drosophila revealed that Huntington's neighborhood is enriched for genetic modifiers, some of them presenting potential targets for therapeutic intervention. A more recent study generated a high confidence interaction data set related to Alzheimer's disease (AD) from well-characterized AD-related gene products and coexpressed candidate proteins encoded in chromosomal regions associated with AD (49). Strikingly, only four out of 200 protein interactions within this set have been reported by other studies.…”

“…Recent studies indicated that gene products associated with a particular phenotype: (i) interact preferentially with proteins involved in the same disease (35), (ii) often exhibit a higher connectivity within the interaction network than nondisease gene products (48,49), (iii) occur in central network locations, and (iv) often share characteristic topological network features with each other (50,51).…”