The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastative neurodegenerative disease characterized by selective loss of motoneurons. While several breakthroughs have been made in identifying ALS genetic defects, the detailed molecular mechanisms are still unclear. These genetic defects involve in numerous biological processes, which converge to a common destiny: motoneuron degeneration. In addition, the common comorbid Frontotemporal Dementia (FTD) further complicates the investigation of ALS etiology. In this study, we aimed to explore the protein-protein interaction network built on known ALS-causative genes to identify essential proteins and common downstream proteins between classical ALS and ALS+FTD (classical ALS + ALS/FTD) groups. The results suggest that classical ALS and ALS+FTD share similar essential protein set (VCP, FUS, TDP-43 and hnRNPA1) but have distinctive functional enrichment profiles. Thus, disruptions to these essential proteins might cause motoneuron susceptible to cellular stresses and eventually vulnerable to proteinopathies. Moreover, we identified a common downstream protein, ubiquitin-C, extensively interconnected with ALS-causative proteins (22 out of 24) which was not linked to ALS previously. Our in silico approach provides the computational background for identifying ALS therapeutic targets, and points out the potential downstream common ground of ALS-causative mutations.

TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis

“…Alternatively, or in addition, since the prion-like domain typically mediates protein-protein interactions, it is possible that shifting the ratio between hnRNP A1 and hnRNP A1B could have consequences on downstream pathways. A recent report suggests that VCP, hnRNP A1, FUS and TDP-43 constitute the core protein-protein interaction network in classical ALS (Mao et al, 2017). That these four proteins could be central in the development of ALS pathology is because of the finding that they interact with the majority of proteins implicated in the disease (Mao et al, 2017).…”

“…A recent report suggests that VCP, hnRNP A1, FUS and TDP-43 constitute the core protein-protein interaction network in classical ALS (Mao et al, 2017). That these four proteins could be central in the development of ALS pathology is because of the finding that they interact with the majority of proteins implicated in the disease (Mao et al, 2017). Since TDP-43 is mislocalized in most ALS cases and half of all FTD cases, studying the targets and the function of hnRNP A1B may provide further insight towards dissecting the network of RNA binding proteins and downstream pathways that contribute to ALS pathogenesis.…”

Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS

“…Therefore, many feel troubled distinguishing real suggestion from a false negative or false positive affirmation. However, recent studies began to utilize IPA and other network analysis to reveal protein dynamics and interactions with respect to disease 7 . To overcome many of the challenges of using large data management toolboxes, we first utilized a very stringent inclusion criteria: only the experimentally observed and previously published direct interactions using neuronal systems are included.…”

“…Genetics offer an important source for understanding the intricate balance between mutation and pathology. Developments in the fields of human genetics, protein detection systems as well as protein interaction assays, and large data management applications have begun to offer a unique opportunity to link genes with proteins and protein interaction networks 7 to reveal the intricate cellular balance that becomes perturbed in the presence of a single mutation. Upon identification of numerous genes that are linked and associated with ALS, revealing the biological link between mutations and neuronal vulnerability has recently became a possibility 8 – 11 .…”

A network analysis revealed the essential and common downstream proteins related to inguinal hernia

“…The main concept is the "centrality-lethality rule", in which highly connected hub proteins with a central role are more essential to survival in the PPI network [34]. Although there is still significant debate regarding this rule, several studies suggest a correlation between topological centrality and protein essentiality [27,37,38]. Additionally, there may be common downstream proteins, which maximally connect with those inguinal hernia-causative proteins through either direct or indirect interaction.…”